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Wake Forest Institute for Regenerative Medicine (WFIRM …

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New Video Series – Watch Now

Scroll down to get an inside look into the lab and hear directly from our scientists about their projects aimed at helping patients with conditions such as diabetes, lung disease, hemophilia A and gastrointestinal disorders.

An International Leader in Regenerative Medicine

The Wake Forest Institute for Regenerative Medicine (WFIRM) is a leader in translating scientific discovery into clinical therapies. Physicians and scientists at WFIRM were the first in the world to engineer laboratory-grown organs that were successfully implanted into humans. Today, this interdisciplinary team is working to engineer more than 30 different replacement tissues and organs and to develop healing cell therapies – all with the goal to cure, rather than merely treat, disease.

The Next Evolution of Medical Treatments

Regenerative medicine has been called the “next evolution of medical treatments,” by the U.S. Department of Health and Human Services. With its potential to heal, this new field of science is expected to revolutionize health care. It is our mission at WFIRM to improve patients’ lives by developing regenerative medicine therapies and support technologies.

“We have many challenges to meet, but are optimistic about the ability of the field to have a significant impact on human health. We believe regenerative medicine promises to be one of the most pervasive influences on public health in the modern era.”-Anthony Atala, MD, Director

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What is Integrative Medicine? – Duke Integrative Medicine

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Integrative medicine is an approach to care that puts the patient at the center and addresses the full range of physical, emotional, mental, social, spiritual and environmental influences that affect a persons health. Employing a personalized strategy that considers the patients unique conditions, needs and circumstances, it uses the most appropriate interventions from an array of scientific disciplines to heal illness and disease and help people regain and maintain optimum health.

Integrative medicine is grounded in the definition of health. The World Health Organization (WHO) defines health as a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity.

Integrative medicine seeks to restore and maintain health and wellness across a persons lifespan by understanding the patients unique set of circumstances and addressing the full range of physical, emotional, mental, social, spiritual and environmental influences that affect health. Through personalizing care, integrative medicine goes beyond the treatment of symptoms to address all the causes of an illness. In doing so, the patients immediate health needs as well as the effects of the long-term and complex interplay between biological, behavioral, psychosocial and environmental influences are taken into account.

Integrative medicine is not the same as alternative medicine, which refers to an approach to healing that is utilized in place of conventional therapies, or complementary medicine, which refers to healing modalities that are used to complement allopathic approaches. If the defining principles are applied, care can be integrative regardless of which modalities are utilized.

The defining principles of integrative medicine are:

In addition to addressing and handling the immediate health problem(s) as well as the deeper causes of the disease or illness, integrative medicine strategies also focus on prevention and foster the development of healthy behaviors and skills for effective self-care that patients can use throughout their lives.

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What is Integrative Medicine? – Duke Integrative Medicine

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Genetics & Medicine – Site Guide – NCBI

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Bookshelf

A collection of biomedical books that can be searched directly or from linked data in other NCBI databases. The collection includes biomedical textbooks, other scientific titles, genetic resources such as GeneReviews, and NCBI help manuals.

A resource to provide a public, tracked record of reported relationships between human variation and observed health status with supporting evidence. Related information intheNIH Genetic Testing Registry (GTR),MedGen,Gene,OMIM,PubMedand other sources is accessible through hyperlinks on the records.

A registry and results database of publicly- and privately-supported clinical studies of human participants conducted around the world.

An archive and distribution center for the description and results of studies which investigate the interaction of genotype and phenotype. These studies include genome-wide association (GWAS), medical resequencing, molecular diagnostic assays, as well as association between genotype and non-clinical traits.

An open, publicly accessible platform where the HLA community can submit, edit, view, and exchange data related to the human major histocompatibility complex. It consists of an interactive Alignment Viewer for HLA and related genes, an MHC microsatellite database, a sequence interpretation site for Sequencing Based Typing (SBT), and a Primer/Probe database.

A searchable database of genes, focusing on genomes that have been completely sequenced and that have an active research community to contribute gene-specific data. Information includes nomenclature, chromosomal localization, gene products and their attributes (e.g., protein interactions), associated markers, phenotypes, interactions, and links to citations, sequences, variation details, maps, expression reports, homologs, protein domain content, and external databases.

A collection of expert-authored, peer-reviewed disease descriptions on the NCBI Bookshelf that apply genetic testing to the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions.

Summaries of information for selected genetic disorders with discussions of the underlying mutation(s) and clinical features, as well as links to related databases and organizations.

A voluntary registry of genetic tests and laboratories, with detailed information about the tests such as what is measured and analytic and clinical validity. GTR also is a nexus for information about genetic conditions and provides context-specific links to a variety of resources, including practice guidelines, published literature, and genetic data/information. The initial scope of GTR includes single gene tests for Mendelian disorders, as well as arrays, panels and pharmacogenetic tests.

A database of known interactions of HIV-1 proteins with proteins from human hosts. It provides annotated bibliographies of published reports of protein interactions, with links to the corresponding PubMed records and sequence data.

A compilation of data from the NIAID Influenza Genome Sequencing Project and GenBank. It provides tools for flu sequence analysis, annotation and submission to GenBank. This resource also has links to other flu sequence resources, and publications and general information about flu viruses.

A portal to information about medical genetics. MedGen includes term lists from multiple sources and organizes them into concept groupings and hierarchies. Links are also provided to information related to those concepts in the NIH Genetic Testing Registry (GTR), ClinVar,Gene, OMIM, PubMed, and other sources.

A project involving the collection and analysis of bacterial pathogen genomic sequences originating from food, environmental and patient isolates. Currently, an automated pipeline clusters and identifies sequences supplied primarily by public health laboratories to assist in the investigation of foodborne disease outbreaks and discover potential sources of food contamination.

A database of human genes and genetic disorders. NCBI maintains current content and continues to support its searching and integration with other NCBI databases. However, OMIM now has a new home at omim.org, and users are directed to this site for full record displays.

A database of citations and abstracts for biomedical literature from MEDLINE and additional life science journals. Links are provided when full text versions of the articles are available via PubMed Central (described below) or other websites.

A digital archive of full-text biomedical and life sciences journal literature, including clinical medicine and public health.

A collection of clinical effectiveness reviews and other resources to help consumers and clinicians use and understand clinical research results. These are drawn from the NCBI Bookshelf and PubMed, including published systematic reviews from organizations such as the Agency for Health Care Research and Quality, The Cochrane Collaboration, and others (see complete listing). Links to full text articles are provided when available.

A collection of resources specifically designed to support the research of retroviruses, including a genotyping tool that uses the BLAST algorithm to identify the genotype of a query sequence; an alignment tool for global alignment of multiple sequences; an HIV-1 automatic sequence annotation tool; and annotated maps of numerous retroviruses viewable in GenBank, FASTA, and graphic formats, with links to associated sequence records.

A summary of data for the SARS coronavirus (CoV), including links to the most recent sequence data and publications, links to other SARS related resources, and a pre-computed alignment of genome sequences from various isolates.

An extension of the Influenza Virus Resource to other organisms, providing an interface to download sequence sets of selected viruses, analysis tools, including virus-specific BLAST pages, and genome annotation pipelines.

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Genetics & Medicine – Site Guide – NCBI

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Genetics of Skin Cancer (PDQ)Health Professional Version …

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Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name “rodent ulcer.”[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma (reddening of the skin) associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (see Figure 2 and Figure 3). They often ulcerate (see Figure 2). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI’s website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Enlarge

Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Enlarge

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Enlarge

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name “rodent ulcer.” With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma). (Refer to the PDQ summary on Skin Cancer Prevention for more information about risk factors for skin cancer in the general population.)

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick Type I or II skin were shown to have a twofold increased risk of BCC in a small case-control study.[2] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[3]

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that nonmelanoma skin cancers (NMSCs) have a heritability of 43% (95% confidence interval [CI], 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[4] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[4]

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the mid-60s.[5-10] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[11-14] however, other studies have contradicted this finding.[15-18] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. (Refer to the BCNS section of this summary for more information.) PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[19] Binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[20,21] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[22,23] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[24] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[25] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[26]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[27,28] PTCH2 displays 57% homology to PTCH1.[29] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[27,30]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[31] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[26,32] The clinical features of BCNS differ more among families than within families.[33] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[34-36]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[31] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[37] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[38-42] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[43]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[44-47] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[47] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[48,49] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[41,45,50] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[51] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[52]

Other associated benign neoplasms include gastric hamartomatous polyps,[53] congenital pulmonary cysts,[54] cardiac fibromas,[55] meningiomas,[56-58] craniopharyngiomas,[59] fetal rhabdomyomas,[60] leiomyomas,[61] mesenchymomas,[62] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[63-65] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[40,41,61]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon -like lesions, while larger lesions demonstrate more classic cutaneous features.[66] Nonpigmented BCCs are more common than pigmented lesions.[67] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[45,50] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[67] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[31] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[45,68,69] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[69] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[45,61] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[70]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[41,45,50,71] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[72,73] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[74] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[41,56] Other reported malignancies include ovarian carcinoma,[75] ovarian fibrosarcoma,[76,77] astrocytoma,[78] melanoma,[79] Hodgkin disease,[80,81] rhabdomyosarcoma,[82] and undifferentiated sinonasal carcinoma.[83]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[84] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[37] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[43,85] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[84,86] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[84] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[87] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[45,88] with higher rates of occurrence in young females.[89]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[50] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[90]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[91,92] fused, splayed or bifid ribs;[93] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[49] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[94]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[95] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[35,36] These mutations were first identified in individuals with childhood medulloblastoma,[96] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[35] SUFU mutations may also be associated with an increased predisposition to meningioma.[58,97] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare probably autosomal dominant genetic disorder associated with BCC, has been outlined in three case series in the literature.[98-100] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[98] Development of BCC occurs in the fourth decade.[98] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[98,100] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[98,99] The genetic basis of Rombo syndrome is not known.

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[101-103] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[104] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[105]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[101] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[106] a twisted/flattened appearance of the hair shaft on electron microscopy,[107] and increased hair shaft diameter on polarizing light microscopy.[103] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[103] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[108,109]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[110] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[111] One report cites an incidence of BCC of 44% by age 55 years in this population.[112] Individuals who inherit two EBS mutations may present with a more severe phenotype.[113] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[110] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[114]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for NMSCs recommends complete skin examinations every 6 to 12 months for life.[125]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer.[126] For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[127] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[127] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[127-129] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[130] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[131] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 20% reduction in the incidence of new BCCs (95% CI, 6%39%; P = .12). The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 438; P =.02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to BCC.

Level of evidence (nicotinamide): 1aii

Treatment of individual BCCs in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[132,133] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[45] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[132,133]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[134] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy): 4

Topical treatment with LDE225, a Smoothened agonist, has also been investigated for the treatment of BCC in a small number of patients with BCNS with promising results;[135] however, this medication is not approved in this formulation by the U.S. Food and Drug Administration.

Level of evidence (LDE225): 1

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[136] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[137] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer (NMSC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation therapy had an increased risk of SCC at the site of previous radiation (OR, 2.94), compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of NMSCs in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] A case-control study of 415 cases and 415 controls showed similar findings; relative to Fitzpatrick Type I skin, individuals with increasingly darker skin had decreased risks of skin cancer (ORs, 0.6, 0.3, and 0.1, for Fitzpatrick Types II, III, and IV, respectively).[31] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) The same study found that blue eyes and blond/red hair were also associated with increased risks of SCC, with crude ORs of 1.7 (95% CI, 1.22.3) for blue eyes, 1.5 (95% CI, 1.12.1) for blond hair, and 2.2 (95% CI, 1.53.3) for red hair.

However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[32,33] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[34] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[34,35] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[36] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[37]

Immunosuppression also contributes to the formation of NMSCs. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[38-41] NMSCs in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[42,43] Additionally, there is a high risk of second SCCs.[44,45] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[44] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[38,46,47] The risk appears to be highest in geographic areas with high UV exposure.[47] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[48] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[38] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[49]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[50] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the middle of the sixth decade of life.[26,51-55]

A Swedish study of 224 melanoma index cases and 944 of their first-degree relatives (FDRs) from 154 CDKN2A wild-type families and 11,680 matched controls showed that personal and family histories of melanoma increased the risk of SCC, with relative risks (RRs) of 9.1 (95% CI, 6.013.7) for personal history and 3.4 (95% CI, 2.25.2) for family history.[56]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in FDRs. In an independent survey-based study of 415 SCC cases and 415 controls, SCC risk was increased in individuals with a family history of SCC (adjusted OR, 3.4; 95% CI, 1.011.6), even after adjustment for skin type, hair color, and eye color.[31] This risk was elevated to an OR of 5.6 in those with a family history of melanoma (95% CI, 1.619.7), 9.8 in those with a family history of BCC (95% CI, 2.636.8), and 10.5 in those with a family history of multiple types of skin cancer (95% CI, 2.729.6). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[57,58] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[59] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[60] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[60]

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic mutation.

Identification of a strong environmental risk factorchronic exposure to UV radiationmakes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, NMSC is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 5 below.

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that NMSC was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.[61]

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Cell Size and Scale – Learn Genetics

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Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It’s even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar “adenine” label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn’t a mistake. First, there’s less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that’s going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Genetics of Prostate Cancer (PDQ)Health Professional …

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Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 180,890 new cases of prostate cancer and 26,120 deaths from the disease are anticipated in the United States in 2016, making it the most frequent nondermatologic cancer among U.S. males.[1] A mans lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patients life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4] African American men have been reported to have more than twice the rate of prostate cancerspecific death compared with non-Hispanic white men.[1] Differences in race-specific prostate cancer survival estimates may be narrowing over time.[5]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8]

The three most important recognized risk factors for prostate cancer in the United States are:

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger, 1 in 48 for men aged 50 through 59 years, 1 in 17 for men aged 60 through 69 years, and 1 in 10 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[9] Because early-onset cancers may result from germline mutations, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[10,11] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[12]

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%.[13] As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[14-18] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[15,19,20] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[16-20] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[21]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[22-24] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[25]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[26] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.052.20) with an affected father only, 2.96 (95% CI, 2.803.13) with an affected brother only, and 8.51 (95% CI, 6.1311.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.2625.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[27] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.03.0; multivariate RR, 1.7; 95% CI, 0.93.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.414.0).[22] Analysis of data from the Women’s Health Initiative also showed that a family history of prostate cancer was associated with an increase in the risk of postmenopausal breast cancer (adjusted HR, 1.14; 95% CI, 1.021.26).[28] Further analyses showed that breast cancer risk was associated with a family history of both breast and prostate cancers; the risk was higher in black women than in white women. Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[22,29] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[30] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[31-34] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[35,36] Individuals meeting the following criteria may warrant referral for genetic consultation:[35-38]

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.93.3) with adjustment for age and ethnicity.[39]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone before puberty do not develop prostate cancer.[40] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[41] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[42] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[43]

(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.015.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[44]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIRbladder, 0.76; SIRrectal, 0.74).[45]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors, including treatment modality. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[44]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[46]

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[47-49]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.03.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.[50]

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 5263) of prostate cancer risk may be accounted for by heritable factors.[13] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 years in MZ twins vs. 6.5 years in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[15] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53-55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56-59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk >2.0) effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a mans lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score 7, PSA 20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate canceraffected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.093.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Linkage to chromosome 17q21-22 and subsequent fine-mapping and targeted sequencing have identified recurrent mutations in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. Multiple studies have confirmed the association between the G84E mutation in HOXB13 and prostate cancer risk. (Refer to the HOXB13 section of this summary for more information.) The clinical utility of testing for HOXB13 mutations has not yet been defined, but studies are ongoing to define the clinical role. For example, a study evaluated 948 unselected men scheduled for prostate biopsy. The G84E mutation was found in three men (0.3%) who had prostate cancer detected on biopsy, although none of the 301 men who had a family history of prostate cancer carried the mutation.[115] Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional moderately to highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.[116]

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[117,118]

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[117,118]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[120] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[121]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[122,123] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[120,122-132] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.11.3) and short GGN length (OR, 1.3; 95% CI, 1.11.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[133] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[134] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.081.69; P = .03).[135]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Mens Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[136] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[134,137,138] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[139] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[140] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[141]

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[142] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[143,144]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[145] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[142,146] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[120,142] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[147] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.012.08; OR, 1.49; 95% CI, 1.032.15).[135] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.092.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.142.68).[148] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[149]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.350.88; OR, 0.57; 95% CI, 0.360.90; OR, 0.55; 95% CI, 0.350.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.942.63).[150] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[151] This study awaits replication.

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[152] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[153] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.111.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[154] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[155] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[156] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[157-161] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[162] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.330.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[163] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[164] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[165]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[166] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[167] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[178] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[179,180]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[182] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[179] (Refer to the GWAS section of this summary for more information.)

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[183] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[184,185] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to scan the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signalsin which allele frequencies deviate significantly in case compared to control populationsare validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[189] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[192]

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,193] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54128.62 Mb, region 2 at 128.14128.28 Mb, and region 3 (containing rs6983267) at 128.47128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[206] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[208] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.936.80; P = 1.20 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.6224.72; P = 1.29 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.646.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.835.33).[214]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[215] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[216]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[217]

In another study, 49 risk SNPs were genotyped in 2,696 Swedish men, and a polygenic risk score was calculated. On the basis of their genetic risk scores, 172 men aged 50 to 69 years with PSA levels of 1 to 3 ng/mL underwent biopsy. Prostate cancer was diagnosed in 27% of these individuals, and 6% had Gleason 7 or higher disease.[218] The utility of this strategy for identifying who should undergo prostate biopsy is yet to be determined.

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[216] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have poor discriminative ability to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%5% of individuals within the population).[219]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[222] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[223-225] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[226] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[224,226] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[227] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

A 2012 study used a novel approach to identify polymorphisms associated with risk.[228] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13a locus previously implicated in cancer developmentassociated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.131.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[229] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[198,238] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Notably, in a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths), no SNP was associated with prostate cancerspecific survival.[239] The authors concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%). As more data regarding rarer variants are generated and validated, the value of inherited variants for therapeutic decision making may be determined.

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.71.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.20.4) for the 5382insC mutation, and 1.3% (95% CI, 1.01.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 430) among carriers and 3.8% among noncarriers (95% CI, 3.34.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 628). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

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Gene Therapy – Learn Genetics

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What Is Gene Therapy?

Explore the what’s and why’s of gene therapy research, includingan in-depth look at the genetic disorder cystic fibrosis and how gene therapy could potentially be used to treat it.

Gene Delivery: Tools of the Trade

Explore the methods for delivering genes into cells.

Space Doctor

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Challenges In Gene Therapy

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Approaches To Gene Therapy

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

Gene Therapy Successes

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Gene Therapy Case Study: Cystic Fibrosis

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy. Retrieved September 23, 2016, from http://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Sep 23] Available from http://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. “Gene Therapy.” Learn.Genetics.December 1, 2012. Accessed September 23, 2016. http://learn.genetics.utah.edu/content/genetherapy/.

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NOVA – Official Website | Epigenetics

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Epigenetics

PBS air date: July 24, 2007

CHEERFUL NEIL DEGRASSE TYSON: Did you ever notice that if you get to know two identical twins, they might look alike, but they’re always subtly different?

CANTANKEROUS NEIL DEGRASSE TYSON: Yep, whatever.

CHEERFUL NEIL DEGRASSE TYSON: As they get older, those differences can get more pronounced. Two people start out the same but their appearance and their health can diverge. For instance, you have more gray hair.

CANTANKEROUS NEIL DEGRASSE TYSON: No. No, I don’t. Identical twins have the same DNA, exact same genes.

CHEERFUL NEIL DEGRASSE TYSON: Yeah.

CANTANKEROUS NEIL DEGRASSE TYSON: And don’t our genes make us who we are?

CHEERFUL NEIL DEGRASSE TYSON: Well they do, yes, but they’re not the whole story. Some researchers have discovered a new bit of biology that can work with our genes or against them.

CANTANKEROUS NEIL DEGRASSE TYSON: Yeah, you’re heavier, and I’m better looking.

CHEERFUL NEIL DEGRASSE TYSON: Yeah, whatever.

NEIL DEGRASSE TYSON: Imagine coming into the world with a person so like yourself, that for a time you don’t understand mirrors.

CONCEPCIN: As a child, when I looked in the mirror I’d say, “That’s my sister.” And my mother would say, “No, that’s your reflection!”

NEIL DEGRASSE TYSON: And even if you resist this cookie-cutter existence, cultivate individual styles and abilitieslike cutting your hair differently, or running fasteruncanny similarities bond you together: facial expressions, body language, the way you laughor dress for an interview, perhaps, when you hadn’t a clue what your sister was going to wear. The synchrony in your lives constantly confronts you.

CLOTILDE: When I see my sister, I see myself. If she looks good, I think, “I look pretty today.” But if she’s not wearing makeup, I say, “My god, I look horrible!”

NEIL DEGRASSE TYSON: It’s hardly surprising because you both come from the same egg. You have precisely the same genes. And you are literally clones, better known, as identical twins.

But now, imagine this: one day, your twin, your clone, is diagnosed with cancer. If you’re the other twin, what can you do except wait for the symptoms?

CLOTILDE: I have been told that I am a high risk for cancer. Damocles’ sword hangs over me.

NEIL DEGRASSE TYSON: And yet, it’s not uncommon for a twin, like Ana Mari, to get a dread disease, while the other, like Clotilde, doesn’t. But how can two people so alike, be so unalike?

Well, these mice may hold a clue. Their DNA is as identical as Ana Mari and Clotilde’s despite the differences in their color and size. The human who studies them is Duke University’s Randy Jirtle.

So, Randy, I see here you have skinny mice and fat mice. What have you done in this lab?

RANDY JIRTLE: Well, these animals are actually genetically identical.

NEIL DEGRASSE TYSON: The fat ones and the skinny ones?

RANDY JIRTLE: That’s correct.

NEIL DEGRASSE TYSON: Because these are huge.

RANDY JIRTLE: They’re huge.

NEIL DEGRASSE TYSON: Can we weigh them and find out?

RANDY JIRTLE: Sure. So if you take this…

NEIL DEGRASSE TYSON: It looks like they can barely walk.

RANDY JIRTLE: They can’t walk too much. They’re not going to be running very far. So that’s about 63 grams.

NEIL DEGRASSE TYSON: 63 grams.

RANDY JIRTLE: Let’s look at the other one.

NEIL DEGRASSE TYSON: So it’s half the weight.

RANDY JIRTLE: Right.

NEIL DEGRASSE TYSON: This gets even more mysterious when you realize that these identical mice both have a particular gene, called agouti, but in the yellow mouse it stays on all the time, causing obesity.

Just look at this.

So what accounts for the thin mouse? Exercise? Atkins? No, a tiny chemical tag of carbon and hydrogen, called a methyl group, has affixed to the agouti gene, shutting it down. Living creatures possess millions of tags like these. Some, like methyl groups, attach to genes directly, inhibiting their function. Other types grab the proteins, called histones, around which genes coil, and tighten or loosen them to control gene expression. Distinct methylation and histone patterns exist in every cell, constituting a sort of second genome, the epigenome.

RANDY JIRTLE: Epigenetics literally translates into just meaning “above the genome.” So if you would think, for example, of the genome as being like a computer, the hardware of a computer, the epigenome would be like the software that tells the computer when to work, how to work, and how much.

NEIL DEGRASSE TYSON: In fact, it’s the epigenome that tells our cells what sort of cells they should be. Skin? Hair? Heart? You see, all these cells have the same genes. But their epigenomes silence the unneeded ones to make cells different from one another. Epigenetic instructions pass on as cells divide, but they’re not necessarily permanent. Researchers think they can change, especially during critical periods like puberty or pregnancy.

Jirtle’s mice reveal how the epigenome can be altered. To produce thin, brown mice instead of fat, yellow ones, he feeds pregnant mothers a diet rich in methyl groups to form the tags that can turn genes off.

RANDY JIRTLE: And I think you can see that we dramatically shifted the coat color and we get many, many more brown animals.

NEIL DEGRASSE TYSON: And that matters because your coat color is a tracer, is an indicator…

RANDY JIRTLE: That’s correct.

NEIL DEGRASSE TYSON: …of the fact that you have turned off that gene?

RANDY JIRTLE: That’s right.

NEIL DEGRASSE TYSON: This epigenetic fix was also inherited by the next generation of mice, regardless of what their mothers ate. And when an environmental toxin was added to the diet instead of nutrients, more yellow babies were born, doomed to grow fat and sick like their mothers.

It seems to me, this has profound implications for our health.

RANDY JIRTLE: It does, for human health. If there are genes like this in humans, basically, what you eat can affect your future generations. So you’re not only what you eat, but potentially what your mother ate, and possibly even what your grandparents ate.

NEIL DEGRASSE TYSON: So how do you go to humans to do this experiment, when you have these mice, and they’re genetically identical on purpose?

RANDY JIRTLE: That’s right.

NEIL DEGRASSE TYSON: So, who is your perfect lab human?

RANDY JIRTLE: Well, then we look for identical humans, which are identical twins.

NEIL DEGRASSE TYSON: Twins, twins.

And that brings us to the reason why we’re showing you Spanish twins. In 2005, they participated in a groundbreaking study in Madrid. Its aim? To show just how identical, epigenetically, they are or aren’t.

MANEL ESTELLER (Spanish National Cancer Center): One of the questions of twins is, “If my twin has this disease, I will have the same disease?” And genetics tell us that there is a high risk of developing the same disease. But it’s not really sure they are going to have it, because our genes are just part of the story. Something has to regulate these genes, and part of the explanation is epigenetics.

NEIL DEGRASSE TYSON: Esteller wanted to see if the twins’ epigenomes might account for their differences. To find out, he and his team collected cells from 40 pairs of identical twins, age three to 74, then began the laborious process of dissolving the cells until all that was left were wispy strands of DNA, the master molecule that contains our genes.

Next, researchers amplified fragments of the DNA, until the genes themselves became detectable. Those that had been turned off epigenetically appear as dark pink bands on the gel. Now, notice what happens when the genes from a pair of twins are cut out and overlapped.

The results are far from subtle, especially when you compare the epigenomes of two sets of twins that differ in age. Here, on the left, is the overlapped DNA of six-year-old Javier and Carlos. The yellow indicates where their gene expression is identical.

On the right, is the DNA of 66-year-old Ana Mari and Clotilde. In contrast to the younger twins, hardly any yellow shines through. Their epigenomes have changed dramatically.

The study suggests that, as twins age, epigenetic differences accumulate, especially when their lifestyles differ.

MANEL ESTELLER: One of the main findings of our research is that epigenomes can change in function of what we eat, of what we smoke, of what we drink. And this is one of the key differences between epigenetics and genetics.

NEIL DEGRASSE TYSON: As the chemical tags that control our genes change, cells can become abnormal, triggering diseases like cancer. Take a disorder like MDS, cancer of the blood and bone marrow. It’s not a diagnosis you’d ever want to hear.

SANDRA SHELBY: When I went in, he started patting my hand, and he was going, “Your blood work does not look very good at all,” and that I had MDS leukemia, and that there was not a cure for it. And, basically, I had six months to live.

NEIL DEGRASSE TYSON: Was epigenetics the reason? Could the silencing of critical genes turn normal cells into cancerous ones? It’s scary to think that a few misplaced tags can kill you. But it’s also good news, because we’ve traditionally viewed cancer as a disease stemming solely from broken genes. And it’s a lot harder to fix damaged genes than to rearrange epigenetic tags. In fact, we already have a few drugs that will work. Recently, Sandra Shelby and Roy Cantwell participated in one of the first clinical trials using epigenetic therapy.

JEAN PIERRE ISSA (M.D. Anderson Cancer Center): The idea of epigenetic therapy is to stay away from killing the cell. Rather, what we are trying to do is diplomacy, trying to change the instructions of the cancer cells, reminding the cell, “Hey, you’re a human cell. You shouldn’t be behaving this way.” And we try to do that by reactivating genes.

SANDRA SHELBY: The results have been incredible, and I didn’t have really any horrible side effects.

ROY CANTWELL: I am in remission. And going in the plus direction is a whole lot better than the minus direction.

NEIL DEGRASSE TYSON: In fact, half the patients in the trial are now in remission. But, while it maybe easier to fix our epigenome than our genome, messing it up is easier, too.

RANDY JIRTLE: We’ve got to get people thinking more about what they do. They have a responsibility for their epigenome. Their genome they inherit. But their epigenome, they potentially can alter, and particularly that of their children. And that brings in responsibility, but it also brings in hope. You’re not necessarily stuck with this. You can alter this.

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Epigenetics & Inheritance

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We used to think that a new embryo’s epigenome was completely erased and rebuilt from scratch. But this isn’t completely true. Some epigenetic tags remain in place as genetic information passes from generation to generation, a process called epigenetic inheritance.

Epigenetic inheritance is an unconventional finding. It goes against the idea that inheritance happens only through the DNA code that passes from parent to offspring. It means that a parent’s experiences, in the form of epigenetic tags, can be passed down to future generations.

As unconventional as it may be, there is little doubt that epigenetic inheritance is real. In fact, it explains some strange patterns of inheritance geneticists have been puzzling over for decades.

Most complex organisms develop from specialized reproductive cells (eggs and sperm in animals). Two reproductive cells meet, then they grow and divide to form every type of cell in the adult organism. In order for this process to occur, the epigenome must be erased through a process called “reprogramming.”

Reprogramming is important because eggs and sperm develop from specialized cells with stable gene expression profiles. In other words, their genetic information is marked with epigenetic tags. Before the new organism can grow into a healthy embryo, the epigenetic tags must be erased.

At certain times during development (the timing varies among species), specialized cellular machinery scours the genome and erases its epigenetic tags in order to return the cells to a genetic “blank slate.” Yet, for a small minority of genes, epigenetic tags make it through this process and pass unchanged from parent to offspring.

Reprogramming resets the epigenome of the early embryo so that it can form every type of cell in the body. In order to pass to the next generation, epigenetic tags must avoid being erased during reprogramming.

In mammals, about 1% of genes escape epigenetic reprogramming through a process called Imprinting.

Epigenetic marks can pass from parent to offspring in a way that completely bypasses egg or sperm, thus avoiding the epigenetic purging that happens during early development.

Most of us were taught that our traits are hard-coded in the DNA that passes from parent to offspring. Emerging information about epigenetics may lead us to a new understanding of just what inheritance is.

Nurturing behavior in rats Rat pups who receive high or low nurturing from their mothers develop epigenetic differences that affect their response to stress later in life. When the female pups become mothers themselves, the ones that received high quality care become high nurturing mothers. And the ones that received low quality care become low nurturing mothers. The nurturing behavior itself transmits epigenetic information onto the pups’ DNA, without passing through egg or sperm.

Gestational diabetes Mammals can experience a hormone-triggered type of diabetes during pregnancy, known as gestational diabetes. When the mother has gestational diabetes, the developing fetus is exposed to high levels of the sugar glucose. High glucose levels trigger epigenetic changes in the daughter’s DNA, increasing the likelihood that she will develop gestational diabetes herself.

LEARN MORE: IMPRINTING

There is no doubt that epigenetic inheritance occurs in plants and fungi. There is also a good case for epigenetic inheritance in invertebrates. While many researchers remain skeptical about the possibility of epigenetic inheritance in mammals, there is some evidence that it could be happening.

(Linaria vulgaris)

Common toadflax and peloric toadflax are identical in every way, except for the shape of their flowers. They are two variants of the same plant with a difference in one gene. But its not a difference in the DNA code. Its an epigenetic difference. And peloric toadflax can pass on this epimutation to its offspring.

(Raphanus raphanistrum)

When radish plants are attacked by caterpillars, they produce distasteful chemicals and grow protective spines. The offspring of caterpillar-damaged radishes also produce these defenses, even when they live in a caterpillar-free environment. The evidence of epigenetic inheritance in this case is indirect, though its highly likely that the information passes from parent to offspring through the reproductive cells.

(Daphnia)

Female water fleas respond to chemical signals from their predators by growing protective helmets. The offspring of helmeted water fleas are also born with helmets – even in the absence of predator signals. This effect continues to the next generation, though the helmets in the grandchildren are much smaller.

Vinclozolin is a fungicide commonly used on grape plants. Feeding vinclozolin to pregnant rats causes lifelong epigenetic changes in the pups. As adults, male offspring have low sperm counts, poor fertility, and a number of disease states including prostate and kidney disease. The great-grandsons of the exposed male pups also have low sperm counts.

Two lines of evidence in this case support epigenetic inheritance. First, the low sperm count persisted into the third generation. Second, the sperm had an abnormally high level of methyl tags (a type of epigenetic tag that usually silences genes). This is the best case for epigenetic inheritance in mammals to date (Feb 2009).

Making a case for epigenetic inheritance in humans remains especially challenging.

Humans have long life spans, making it time consuming to track multiple generations. Humans have greater genetic diversity than laboratory strains of animals, making it difficult to rule out genetic differences Ethical considerations limit the amount of experimental manipulation that can take place.

But we do have a few hints that suggest that it could be happening.

Geneticists analyzed 200 years worth of harvest records from a small town in Sweden. They saw a connection between food availability (large or small harvests) in one generation and the incidence of diabetes and heart disease in later generations.

The amount of food a grandfather had to eat between the ages of 9 and 12 was especially important. This is when boys go through the slow growth period (SGP), and form the cells that will give rise to sperm. As these cells form, the epigenome is copied along with the DNA. Since the building blocks for the epigenome come from the food a boy eats, his diet could impact how faithfully the epigenome is copied. The epigenome may represent a snapshot of the boys environment that can pass through the sperm to future generations.

Proving epigenetic inheritance is not always straightforward. To provide a watertight case for epigenetic inheritance, researchers must:

Researchers face the added challenge that epigenetic changes are transient by nature. That is, the epigenome changes more rapidly than the relatively fixed DNA code. An epigenetic change that was triggered by environmental conditions may be reversed when environmental conditions change again.

Three generations at once are exposed to the same environmental conditions (diet, toxins, hormones, etc.). In order to provide a convincing case for epigenetic inheritance, an epigenetic change must be observed in the 4th generation.

Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment – without changing its DNA code.

Fish, E.W., Shahrokh, D., Bagot, R., Caldji, C., Bredy, T., Szyf, M., and Meaney, M.J. (2004).Epigenetic programming of stress responses through variations in maternal care. Annals of the New York Academy of Science 1036: 167-180 (subscription required).

Youngson, N.A. and Whitelaw, E. (2008).Transgenerational epigenetic effects. Annual Reviews in Genomics and Human Genetics 9: 233-57 (subscription required).

Kaati, G., Bygren, L.O., Pembrey, M., and Sjostrom, J. (2007).Transgenerational response to nutrition, early life circumstances and longevity. European Journal of Human Genetics 15: 784-790.

Chong, S., and Whitelaw, E. (2004).Epigenetic germline inheritance. Current Opinion in Genetics & Development. 14: 692-696 (subscription required).

APA format:

Genetic Science Learning Center. (2013, July 15) Epigenetics & Inheritance. Retrieved September 23, 2016, from http://learn.genetics.utah.edu/content/epigenetics/inheritance/

CSE format:

Epigenetics & Inheritance [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2013 [cited 2016 Sep 23] Available from http://learn.genetics.utah.edu/content/epigenetics/inheritance/

Chicago format:

Genetic Science Learning Center. “Epigenetics & Inheritance.” Learn.Genetics.July 15, 2013. Accessed September 23, 2016. http://learn.genetics.utah.edu/content/epigenetics/inheritance/.

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QMB Stem Cells and Regenerative Medicine Satellite …

Posted: September 23, 2016 at 4:49 am

QMB Stem Cells and Regenerative Medicine Satellite 28-29th August 2016 Rutherford Hotel, Nelson

Programme here

Assoc Prof Alan Davidson (Auckland) – Stem Cells Assoc ProfTim Woodfield (Otago Uni- Chch) – Regen Med

Translational Regenerative Medicine: Global challenges and opportunities. Biofabrication of functional tissues for Regenerative Medicine Pluripotency, ES cells, and iPSCs Adult stem cells Disease modelling in iPSCs

Sir John Gurdon, University of Cambridge Dr Alan Davidson, University of Auckland Prof Duanqing Pei, Guangzhou Institute of Biomedicine and Health Prof Nadia Rosenthal, The Jackson Lab, Maine Prof Yinxiong Li, Guangzhou Institute of Biomedicine and Health Prof Ernst Wolvetang, University of Queensland Prof Richard Oreffo, University of Southampton, UK Assoc Prof Xuebin Yang, University of Leeds, UK Prof Justin Cooper-White, University of Queensland Prof Wayne McIlwraith, Colorado State University, US Prof Jillian Cornish, University of Auckland, NZ Assoc Prof Tim Woodfield University of Otago Christchurch, NZ

Delegates to this meeting may also be interested in the following conference: Stem Cell Society Singapore Symposium 2016 Modeling Cell Fate & Development 7 8 November 2016, Singapore

For more information about the venue arrangements or regarding conference registration contact our conference management provider Dinamics.

Contact: alastair@dinamics.co.nz Website: http://www.dinamics.co.nz

Key Dates:

Friday 15 July, 2016

Early bird registration deadline

Friday 15 July, 2016

Abstract submission deadline

Friday 22 July, 2016

Awards extended deadline

QRW Updates:

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