Monthly Archives: April 2022

High blood pressure means the force of blood flowing through your arteries is greater than it should be. If not controlled, it could damage your blood vessels and cause other health problems.

High blood pressure (hypertension) tends to be a condition we associate with being too sedentary or getting older. But high blood pressure can also be a genetic condition, affecting people who are otherwise fit and healthy.

A parent with high blood pressure can pass along a gene to a child, raising that persons risk of developing hypertension one day. Familial hypertension may also result from a family lifestyle that includes high blood pressure risk factors, such as smoking or an unhealthy diet.

Blood pressure is the force of circulating blood against the inner wall of your arteries. Its measured in millimeters of mercury (mm Hg) and is presented as two numbers:

According to the American Heart Association, healthy blood pressure is a systolic pressure of less than 120 mm Hg and a diastolic pressure of less than 80 mm Hg. This is a blood pressure of less than 120/80 mm Hg.

If your blood pressure is higher than that, doctors consider you to have elevated blood pressure or stage 1 or 2 hypertension.

Risk factors for high blood pressure include a family history of hypertension, as well as:

What makes high blood pressure so dangerous is that it can exist for a long time without presenting any obvious symptoms. Measuring your blood pressure is the only way to know if you have hypertension.

In extreme cases, when blood pressure exceeds 180/120 mm Hg, you have a medical emergency known as a hypertensive crisis. Symptoms can include:

Research from 2017 suggests that high blood pressure results from a combination of factors, including genetic, environmental, and behavioral components.

Unlike some diseases with only one or a few genes as risk factors, familial hypertension can result from variations in hundreds of different genes, according to a 2019 study of more than 750,000 individuals. This makes it difficult to pinpoint specific genes that could be treatment targets.

The Centers for Disease Control and Prevention (CDC) also notes that families may affect a persons hypertension risk because of the home environment.

Smoking or even breathing in secondhand smoke can raise blood pressure risks. A diet high in sodium and saturated fat may also cause a blood pressure increase. If physical activity and good sleeping habits arent part of a family dynamic, blood pressure can also be negatively affected.

Monogenic hypertension refers to blood pressure caused by one genetic variant inherited from a parent. Monogenic hypertension accounts for about 30 percent of hypertension cases. Most of those are associated with imbalances of electrolytes, such as potassium.

There are several types of monogenic hypertension syndromes, each with a unique set of origins and symptoms. These include:

Knowing about your family medical history is important for many reasons. A history of certain cancers, for example, may determine when you get screened for those cancers. If high blood pressure runs in your family, its important to share this information with your doctor and regularly monitor your blood pressure.

One way to organize information about your family health history, as well as your own, is to use My Family Health Portrait, an online tool created by the National Institutes of Health. You can gather your family medical history, share it with other relatives, and learn about your risk levels for conditions that tend to run in families.

If your blood pressure is currently at a healthy level, you can make several key lifestyle adjustments to lower the odds of it rising too much. If your blood pressure is higher than usual, these steps, along with medications, may help you bring it back down to a healthy range:

The National Heart, Lung, and Blood Institute developed the Dietary Approaches to Stop Hypertension (DASH) eating plan as a heart-healthy eating strategy.

This plan focuses on managing blood pressure by emphasizing fruits, vegetables, whole grains, lean proteins, and sodium reduction. Its also flexible enough to let people enjoy many of their favorite foods.

Sufficient sleep is essential to good overall health, especially for brain and heart function. Blood pressure is especially susceptible to problems related to poor sleep.

A 2022 study suggests that frequent sleep disturbances and short sleep, or less than 5, 6, or 7 hours, can contribute to hypertension.

Taking steps to improve sleep duration and quality may improve more than just your cardiovascular health. It can also improve your mood, concentration, energy, metabolism, and more.

Hypertension is a major risk factor for cardiovascular disease, the leading cause of death in the United States. High blood pressure is also a leading cause of stroke and a risk factor for chronic kidney disease and other health problems.

If your family medical history includes high blood pressure, start taking steps to lower your risk through heart-healthy behaviors. Even if you dont know your family history or dont have a close relative with hypertension, its still important to take steps to keep your blood pressure under control.

Theres a variety of anti-hypertensive medications that can help. But these medications dont take the place of a healthy diet, exercise, and getting plenty of sleep to help maintain a healthy blood pressure.

Read this article:
Familial Hypertension: The Genetics of High Blood Pressure - Healthline

In PLOS Genetics, researchers from Texas A&M University and Colorado State University describe host genetics-related survival differences in mouse models of infection with the Salmonella enterica serovar Typhimurium, which causes typhoid fever. Using nearly three dozen genetically distinct mouse strains from the Collaborative Cross collection, the team tracked clinical features and outcomes in the days following oral infection with S. Typhimurium. Along with lower-than-usual body temperatures and activity levels prior to infection, the authors linked survival to new and known risk loci on chromosomes 1, 2, 4, and 7. "We identified a broad range of outcomes across these different mice, including a group of mice susceptible to lethal infection and a group that survived our [seven] day study," the authors write, noting that the study "defines the utility of exploring how host genetic diversity influences infection outcomes with bacterial pathogens."

For another paper in PLOS Genetics, a team from the Huazhong University of Science and Technology and other centers in China and the US present evidence of altered RNA splicing in lung tissues from nine fatal COVID-19 cases from the initial Wuhan wave and 10 control samples. With a combination of proteomic profiling and transcriptome sequencing, the researchers saw transcript splicing shifts and alternative transcript usage, particularly when it came to genes related to blood coagulation, immune function, and antiviral activity. "[T]he dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity," they report, noting that "SARS-CoV-2 proteins directly engage host spliceosome to dysregulate essential steps of mature mRNA production and result in widespread dysregulation of cellular function."

Investigators reporting in PLOS One describe apparent genetic ties between intracranial aneurysm and acute ischemic stroke in individuals from Korea, demonstrating with the development of a polygenic risk score (PRS) linked to the risk of both conditions. The team settled on a PRS model for predicting intracranial aneurysm by analyzing weighted PRS models established using data from a prior genome-wide association study that included more than 470 intracranial aneurysm or acute ischemic stroke cases, and nearly 300 unaffected controls, subsequently linking the resulting PRS to elevated risk of acute ischemic stroke as well. Based on these and other results, the authors suggest that intracranial aneurysm and acute ischemic stroke "may have a shared genetic architecture and should be studied further to generate a precision medicine model for use in personalized diagnosis and treatment.

See more here:
PLOS Papers on Typhoid Fever Host Genetics, COVID-19-Related RNA Splicing, More - GenomeWeb

Introduction

Cancer has been one of the leading causes of human death. According to estimates, more than 220 thousand new cases of lung cancer will occur in the United States in 2020.1 In general, lung cancer is subdivided into two categories, of which small cell lung cancer (SCLC) represents about 1315%. At diagnosis, about 80% of patients with SCLC are in an advanced stage and cannot undergo surgery.2

SCLC is a highly heterogeneous malignant neuroendocrine tumor.3 Small cell transformation has been demonstrated to be one of the ways in which non-small cell lung cancer (NSCLC) develops resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), leading to a poor prognosis.4 Although TP53 and RB1 are tumor suppressor genes with high incidence, few genetic driver events have been reported.5 Recent evidence reveals that immune checkpoint inhibitors (ICIs) and specifically programmed death ligand 1 inhibitors combined with standard platinum/etoposide can enhance progression-free survival with minimal adverse effects in patients with extensive SCLC.6,7 Furthermore, recent evidence shows that co-stimulatory B7-H3 may act as an independent prognostic indicator for SCLC cases, which might provide a theoretical basis for subsequent research targeting B7-H3.8,9

FOXM1 is crucial for SCLC tumorigenesis and is associated with a poor prognosis. After standard chemotherapy, patients with high FOXM1 expression had shorter progression-free survival compared to those with low FOXM1 expression (3.90 vs 8.69 months).10 In vitro experiments and experiments on xenograft (PDX) models derived from SCLC patient-derived xenograft reveal that pharmacological inhibition of DHODH can suppress the cell viability.11 Therefore, in SCLC treatment, DHODH has been a promising target.

SCLC is prone to develop chemoresistance due to its intratumoral heterogeneity.12 Despite recent advances, SCLC remains the most lethal lung cancer with limited therapeutic options. Studies report that patients with SCLC have a poor prognosis, except for a minimal number of early-stage cases.13

Accumulated studies demonstrate that SCLC is a highly heterogeneous tumor, although fewer genetic colonies have been reported comparison with NSCLC. Transcriptomic analyses reveal four different molecular subtypes, including SCLC-A driven by the transcription factor ASCL1, SCLC-N driven by NEUROD1, SCLC-Y by YAP1 and SCLC-P by POU2F3,14 allowing for more targeted therapeutic approaches. Subsequent studies confirmed that a unique YAP1 subtype did not exist, and an inflamed subtype of SCLC (SCLC-I) was recently proposed to replace YAP1 subtype.15 Although SCLC-I subtype experienced the greatest benefit from immune checkpoint inhibitor therapy, the clinical significance of this molecular subtyping in guiding treatment and estimating prognosis remains limited to other standard SCLC treatments.

The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC, including TP53 and RB1 inactivation and frequent chromosomal abnormalities (deletion 3p).16 In addition to the inactivated Notch pathway, MYC family amplification has a high incidence.17 Few druggable targeted molecules can be used in clinical practice.18 Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. Therefore, it is essential to investigate the genetic characteristics of SCLC and their clinical implications.

In this study, 18 cases of pathologically proven SCLC cases were sequenced using a panel of 520 cancer-related genes. The average median sequencing depth of the samples was 1260x. The average median q30 ratio of the samples was 91%, and all samples are qualified. Analyzing the sequencing results and pathological data revealed some genetic variants with distinctive characteristics.

SCLC presents a distinctive mutation spectrum compared to adenocarcinoma. In our cohorts, results reveal 72% cooccurring TP53/RB1 mutations. Furthermore, in the samples of small cell lung cancer, the core 8 gene was not detected. In SCLC, the frequency of gene mutations is significantly lower than in adenocarcinoma. The mutation frequency of Rb1, MSH6, KDR, IL7R, ATRX, EPHB1, PDGFRA and KIT in SCLC is markedly higher than those in lung squamous cell carcinoma. Due to the small sample size, it might be affected by some random factors.

Patients diagnosed with SCLC at Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, were enrolled in this study after obtaining informed consent. Biopsy specimens of advanced stage SCLC were obtained from the Department of Pathology Affiliated Cancer Hospital of Zhengzhou University. The study protocols were approved by the institutional ethics review board (Ethics Review Committee, Zhengzhou University). While collecting specimens for analysis, we complied with the declaration of Helsinki (2013 Edition) and relevant regulations. Additionally, the clinical characteristics were recovered in this research.

DNA extraction and targeted sequencing were performed in Burning Rock Biotech as described in the previous protocol.19,20 In brief, formalin-fixed, paraffin-embedded (FFPE) specimens were used for DNA extraction through QIAamp DNA kit (Qiagen, Germany). Subsequently, DNA purification, hybridization and amplification were performed. Target capture was conducted through a commercial 520 genes panel (OncoScreen Plus). The quality of fragments was determined using a Bioanalyzer 2100 (Agilent Technologies, USA). Finally, the samples were sequenced via the platform of nextseq 500 (Illumina, Inc., USA).

The reference genome Hg19 was used through Burrows-Wheeler Aligner version 0.7.10.21 Subsequently, sequence alignment and variant calling were performed through programs including varscan version 2.4.3 and the genome analysis tool kit version 3.2.22 The genes variants were annotated with ANNOVAR.23 The structural variations (SVs) were analyzed using Factera version 1.4.3.24

It should count as mutations that non-synonymous single nucleotide variants (SNVs) and indels in the coding sequences and two adjacent base pairs around these regions, while hot mutation, copy number variations (CNVs), structural variations (SVs), and SNPs were excluded.

The size of coding sequences required to estimate TMB is 1.003 MB in the 520 gene panel. The MB per patient was calculated using the following formula.

Table 1 lists the clinical and pathological information of SCLC patients. Prospective follow-up was conducted through routine hospital visits or telephone calls. Once every three months, trained medical staff made telephone calls to patients or their family members until death or the last follow-up. The follow-up data of this cohort is included in the Supplementary Materials. Overall survival (OS) was estimated from the day of SCLC diagnosis to the day of death from any cause and was analyzed using KaplanMeier estimates and Log rank test. The correlations between categorical variables were calculated using Chi-squared and Fishers exact tests. Statistical analyses were performed using SPSS23.0, and P 0.05 was considered statistically significant.

Table 1 Clinicopathological Characteristics of the 18 SCLC Patients

Capture-based targeted sequencing was performed by Burning Rock Biotech, Guangzhou, China. The average median sequencing depth of the samples was 1260x, consistent with expectations. The average median q30 ratio of the samples was 91%, and all samples were qualified (Supplementary Figure 1). The deletion of the tumor suppressor genes TP53 and RB1 has long been recognized as a common mutation in SCLC. Out of 18, 13 patients showed a co-mutation of TP53 and RB1, reaching a mutation rate of 72%, and the remaining five patients were found with wild-type RB1 as displayed in Figure 1A. Other frequent mutant genes are LRP1B, FAT3, KMT2D, KDR, PTEN, SPTA1, MSH6, Bcl6, EPHB1, etc. Figure 1B illustrates the distribution of identified mutations in SCLC.

Figure 1 Mutation landscape of SCLC. (A) Genomic alteration profiling. X axis is specific specimens and Y axis is the detected mutations for a different gene. The percentage of mutation of a specific gene in total patients. (B) Distribution of mutations in SCLC.

The genetic alteration observed in our cohort was in accordance with the SCLC database of Burning Rock Biotech (RS_SCLC) (Figure 2A). Figure 2A includes genes detected in at least three samples. The gene mutation frequency in this cohort did not differ significantly from that in RS_SCLC database.

Figure 2 (A) Genetic alteration in our cohort consistent with Burning Rock Biotech SCLC database (RS_SCLC). (B) Genetic differences between SCLC and non-small cell lung cancer (NSCLC) (C). Single nucleotide variation analysis. *in (B and C) represents statistically significant differences (p < 0.05). **in (B and C) represents statistically significant differences (0.01

The genetic differences between SCLC and non-small cell lung cancer were further analyzed (Figure 2B) to explore the molecular genetic characteristics of SCLC. In comparison with NSCLC (adenocarcinoma and squamous cell carcinoma), the mutation spectrum of SCLC differed significantly from the adenocarcinoma database of Burning Rock Biotech (RS_LUAD). Neither the core eight gene nor the frequent mutations in SCLC were detected in adenocarcinomas. Compared to Burning Rock Biotechs database of squamous cell carcinoma (RS_LUSC), the mutation frequency of genes RB1, MSH6, KDR, IL7R, ATRX, EPHB1, PDGFRA, and KIT was significantly higher. Considering the small sample size, other factors might affect it.

Furthermore, a single nucleotide variation analysis revealed that C > A mutations were more frequent in SCLC, whereas C > T mutations were significantly lower, as illustrated in Figure 2C. Moreover, we analyzed the gene copy number variation (CNV) and tumor mutation burden (TMB) in our cohorts (Figure 3). There was no significant difference in gene copy number variation (CNV) between the cohorts of SCLC group and RS_LUSC group (P = 0.54). In contrast, there was a significant difference between SCLC and RS_LUAD groups (P = 0.014). In terms of tumor mutation burden (TMB), there was no significant difference between cohorts of SCLC and RS_LUSC groups (P = 0.80), whereas there was a considerable difference between SCLC and RS_LUAD groups (P = 0.003). In general, SCLC showed higher copy number amplification and TMB compared to lung adenocarcinomas.

Figure 3 Gene copy number variation (CNV) (A) and tumor mutation burden (TMB) (B) in our SCLC cohort differ from lung adenocarcinoma.

In the final analysis, we examined the association between gene mutation and clinicopathological data, including gender, smoking, specimen origins, metastasis site, progression-free survival and overall survival (Figure 4). The criteria for gene inclusion were as follows: a. genes detected in at least three samples, b. clinical factors with at least three statistics, c. baseline sample data were included for analysis. The results revealed a significant correlation between several mutant genes and clinical factors. The KaplanMeier curve showed that patients with LRP1B (Figure 5A) or MAP3K13 (Figure 5B) mutation exhibited significantly shortened PFS.

Figure 4 The correlation between mutant gene and clinicopathological data including gender, smoking, specimen origins, metastasis site, and progression free survival and overall survival. Red indicates statistically significant differences (p < 0.05).

Figure 5 KaplanMeier curve indicated that SCLC patients with LRP1B (A) or MAP3K13 (B) mutation had significantly shorter PFS. SCLC patients with MSH6 mutation had significantly longer OS (C) while OS was significantly shorter in patients with SPEN mutation (D).

Moreover, SCLC patients with MSH6 mutation had significantly longer OS (Figure 5C), while the OS decreased significantly in patients with SPEN mutation (Figure 5D). In conclusion, MSH6 mutations are associated with a better prognosis than SPEN mutations. The results of this study may help to diagnose and treat Chinese SCLC patients.

The proportion of mutant-PIK3CA was higher in patients with bone metastases (P = 0.012), and the proportion of mutant-FAT1 was higher in patients with liver metastases (P = 0.044), as displayed in Figure 6. Of 18, five patients eventually developed bone metastases; three were detected with PIK3CA mutation, while five of the patients with liver metastases were detected with FAT1 mutation. Based on these results, it can be concluded that related signaling pathways could play a role in regulating organ-specific metastasis.

Figure 6 The proportion of mutant-PIK3CA is higher in patients with bone metastases (A), the proportion of mutant-FAT1 is higher in patients with liver metastases (B).

The signaling pathways based on KEGG involved in mutant genes were analyzed (Figure 7). A pathway is deemed mutant when at least one sample has a mutation in it. Signaling pathways with statistical correlations are listed in Table 2, which requires further investigation. The results indicated that HIF1 signaling pathway, estrogen signaling pathway, chemokine signaling pathway and T cell receptor signaling pathway contributed to bone and lymph node metastasis. Additionally, signaling pathways linked to PFS and OS were identified, and these findings may provide genetic explanations for clinicopathological features.

Table 2 The Clinical Factors are Associated with Signaling Pathway Based on KEGG Pathway to Some Extent

Figure 7 The correlation between signaling pathways involved in mutant genes (based on KEGG pathway) and clinicopathological data including gender, smoking, specimen origins, metastasis site, and progression free survival and overall survival. Red indicates statistically significant differences (p < 0.05).

SCLC in the early stages is sensitive to radiotherapy and chemotherapy. In most patients, satisfactory treatment results cannot be achieved due to the diseases early progression, recurrence, and chemotherapy resistance. Despite recent advances in SCLC, even on standard platinum-containing two-drug chemotherapy combined with immunization, survival did not exceed two years.25 Nitin Roper et al disclosed that different transcriptional SCLC subtypes could experience clinical benefit to ICIs, as was Notch signaling activation, which might provide the means for more effective application of ICIs in SCLC.26 Chemo-immunotherapy has become the preferred initial treatment for advanced SCLC, but only a small subset of SCLC patients benefits from ICIs, and there is an urgent need for biomarkers with efficient prediction.27

SCLC has long been considered to have higher genomic instability than other types of cancer.28 The inactivation of TP53 and RB1 occurs early in the course of SCLC.29 Inactivation of RB1 allows cells to enter the cell cycle, while TP53 loss can prevent cell cycle arrest and apoptosis. Amplification of Myc family members may enhance cell proliferation, while ASCL1 promotes neuroendocrine fate.30

Furthermore, studies have found that histone modification is highly prevalent in SCLC. Overall, these genetic alterations result in replication stress in SCLC, providing a potential direction for gene intervention therapy. Therefore, the study examined various gene mutations associated with SCLC and the effects of those mutations on the pathogenesis of clinical events and their prognosis. In the cbioportal site, we observed whole-genome sequencing of 120 small cell lung cancer (SCLC) tumour samples and matched normal materials.31 The tumour samples in this study were enriched for earlier stages, while tumour samples were all advanced stages in our study. Surgical treatment is considered for less than 5% of early patients limited to the lung parenchyma for SCLC patients. Then, therapeutic options are completely different. The differences in treatment outcomes were not comparable, but there were no significant differences in the frequency of key gene mutation (P53,RB), diagnosis age and sex ratio, indicating that our cohort is representative to some extent.

It is worth mentioning that KaplanMeier curve suggested that SCLC patients with LRP1B or MAP3K13 mutation had shorter PFS in our study. LRP1B (low-density lipoprotein receptor-related protein 1b) is a putative tumor suppressor. Recent evidence suggests that LRP1B might be a genetic marker for immune checkpoint inhibitors (ICI) in multiple types of cancers.32,33 However, nuclear LRP1B, which was released by the intracellular LRP1B domain and transported to the nucleus, increased the invasion activity of breast cancer cells by upregulation of NEAT1.34 Further studies are required to understand the molecular significance of LRP1B in SCLC progression. MAP3K13 (encoding LZK) is an amplified driver gene in head and neck cancer cells and plays a crucial role in maintaining mutant p53 expression.35 Qiang Zhang36 revealed a regulatory pathway that supervised Myc protein stability via MAP3K13-TRIM25-FBXW7 signaling axis, suggesting a potential therapeutic target for cancers that over-express Myc. Considering that MAP3K13 is a targetable oncogenic kinase, its clinical application deserves further investigation in SCLC.

Researchers found that MSH6 mutations have a better prognosis compared to SPEN mutations. DNA mismatch repair genes (MMR) function in maintaining genomic stability. The dysfunction of MMR genes could lead to accumulation during the repair process of DNA and lead to gene instability and overexpression of cancer-related genes, causing tumor initiation and progression.37 Nine MMR genes related to human mismatch repair have been isolated from human bacteria. MMR is a bacterial MUTS homologue and mainly forms a mismatch complex with MSH2 (MSH2-MSH6) to play a role in mismatch repair.38,39

SPEN family transcriptional repressor (SPEN), also known as SMART/HDAC1-related repressor protein, can regulate transcription and is essential for X chromosome inactivation.40,41 Multiple studies have demonstrated that SPEN can perform different functions in tumorigenesis. SPEN mutation alters a protein complex that represses the transcription of chronic lymphocytic leukemia NOTCH1 target genes.42 SPEN induces miR-4652-3p expression by activating PI3K/AKT/c-JUN signaling to target HIPK2.43 High levels of SPEN RNA are associated with early metastasis in two independent cohorts of 77 (HR 2.25, P = 0.03) and 170 (HR = 2.23, P = 0.004) patients with ER-negative breast cancer.44 In contrast, SPEN is a tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ER-positive breast cancers.45 In colon cancer, it acts as an oncogene for its pathogenesis, since it positively regulates Wnt signaling.46 However, the molecular mechanism of SPEN in SCLC remains unknown. In our cohort, the OS of SCLC patients with SPEN mutation decreased significantly, indicating that SPEN could be used as a prognostic biomarker.

PI3K/Akt-mediated pathways have been implicated in many tumors. PIK3CA is a P110 catalytic subunit of phosphatidylinositol-3 kinases (PI3Ks), which encodes the PIK3CA protein, namely PI3KP110A.47 PIK3CA plays a role in multiple signaling pathways and controls cellular functions.48 Among them, PIK3CA encoding PI3KP110A is the only oncogenic gene with somatic mutation among the members of the PI3K family found at present. About 4/5 mutations of PIK3CA occur in two hot spots, the helix region (Exon 9) and the kinase region (Exon 20).49 PIK3CA has been identified as an oncogene based on its function and genetics. In tumor cells, the pathogenic mutation of PIK3CA causes abnormal encoding of the p110 subunit that leads to continuous activation of PI3K enzyme. Furthermore, it can activate the downstream Akt, causing independent cell proliferation and enhancing the ability of cells to metastasize.50,51 A series of PIKK3CA mutations have been reported in various cancer lines, including SCLC (3.44.3%), colorectal cancer (3040%), ovarian cancer, thyroid,52,53 cancer,54 gastric cancer, and breast cancer (740%).55 This gene has also been targeted in previous studies of SCLC. Triciribine, a small-molecule Akt inhibitor, was found to act as a pathway inhibitor and was more sensitive to SCLC types with PIK3CA mutations.56 In this study, three samples had PIK3CA mutations, and all of them had bone metastases, resulting in a poor prognosis for the patients. Further studies are needed to understand how this gene could improve the treatment of patients with SCLC.

FAT1 is a member of the cadherin superfamily, which encodes procadherin and is frequently mutated in human cancers, especially squamous cell carcinoma.57,58 Similarly, our results also showed that nonsense mutations of FAT1 are common and can cause loss of gene function. Previous studies have linked FAT1 mutations to poor outcomes in cancer patients. Recurrent somatic mutation of FAT1 in multiple human cancers could result in aberrant Wnt signaling activation, thus promoting the tumor progression.59,60 Studies have demonstrated that FAT1 can encode a protein that binds to -catenin and antagonizes -catenin to enter cells to target and activate Wnt that can inhibit cell proliferation and tumor growth.61 The experiments on constructed mouse models of skin squamous cell carcinoma and lung cancer found that loss of FAT1 can inhibit adhesion and promote epithelial to mesenchymal cell transformation (EMT) and thus promote tumor genesis, development and metastasis.62 From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with the top mutated genes TP53 and CASP8. Poor overall survival or progression-free survival was observed in patients with FAT1 mutation or altered HER3_pY1289, IRS1, or CAVEOLIN. Pathway analysis revealed dominant ERBB/neuregulin pathways mediated by FAT1 mutations in HNSCC.63 FAT1 plays various roles in different types of cancer and can be used as an oncogene or a tumor suppressor gene. Studies have confirmed that the expression of FAT1 in liver cancer is higher and acts as a tumor protector than in nontumor liver tissue.64,65 Our results show that patients with FAT1 mutation were more prone to liver metastasis, an alternative therapeutic target for SCLC patients. Farago et al reported that combining olaparib and temozolomide in relapsed SCLC could significantly improve the prognosis of SCLC patients.66 After that, they identified a molecular signature predictive of the response to this regimen. Olaparib is PARP inhibitor and has been proved to be effective for BRCA-mutated metastatic breast cancer and ovarian cancer.67,68 We found BRCA2 mutant in our SCLC cohort, which might suggest better sensitivity to olaparib.

Next-generation sequencing demonstrates that the genetic landscape of SCLC is different from that of adenocarcinoma and squamous cell carcinoma. Part mutant genes are linked to clinical factors to some extent. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. Oncologists might acquire important information to assist in therapeutic options and prognosis evaluation, and SCLC patients might benefit from NGS in clinical practice, and the underlying mechanism deserves further investigation.

We are grateful to all peer reviewers and editors for their opinions and suggestions.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

This work was supported by grants from Henan Cancer Hospital Doctors Initiation Foundation (Grant No. 310103010210962) and Medical Science and Technology Research Program of Henan Province (Grant No. LHGJ20190636). Natural Science Foundation of Henan Province (Grant No.222300420353).

The authors declare that they have no conflicts of interest in this work.

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Genetic Alteration and Their Significance on Clinical Events | CMAR - Dove Medical Press

Market Situation

In the course of the study, the researchers took a look at the use of COVID-19 on company operators, allies, and disruptors. Because of the wide availability of locks in different areas and nations, the results may vary significantly across sections and regions. Research studies both short- and long-term industrial impacts, and also assists in helping governments formulate short- and long-term business strategies for each specific geographic area.

The Global Animal Genetics Market analysis report is the outcome of incessant efforts guided by knowledgeable forecasters, innovative analysts and brilliant researchers. With the specific and state-of-the-art information provided in this report, businesses can get idea about the types of consumers, consumers demands and preferences, their perspectives about the product, their buying intentions, their response to particular product, and their varying tastes about the specific product which is already present in the market. By providing an absolute overview of the market, Animal Genetics Market report covers various aspects of market analysis, product definition, market segmentation, key developments, and the existing vendor landscape.

In addition to investigating external factors, which are anticipated to have a good or unfavorable effect on the company, an analyst evaluates internal elements to give decision-makers a solid long-term prognosis for the industry. An analysis may examine market segments and forecast the size of the worldwide market. The findings reveal that investment prospects gain greater insight when conducting a competitive analysis, developing their product profile, evaluating prices, gauging a companys financial position, laying out a long-term development strategy, and discussing their footprint on the global market of the Animal Genetics.

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Animal Genetics Market Report Scope

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The growth of this business is very new, and as a result, it exacerbates many of the risks. This article details many of the issues faced by the industry, and I have included it here as a reference. While we generally focus on the law and smart city regulations, our specific interests are Animal Genetics. SWOT Review and Market Strategies have an effect on prominent industry players. According to the study, the report looks at leaders in the sector, including information on companies, products and services, and information given over the past four years, which is a significant shift over the previous five years.

Players Stance

The study provides a list of the top Animal Genetics industry players whose SWOT analysis and market strategies were impacted by the research. Additionally, the research focuses on knowAnimal Geneticsge leaders, such as company profiles, goods, and services that have produced financial data during the last four years, a substantial change from the prior five years:

Animal Genetics Market Segmentations:

Global Animal Genetics Market: Type Segment Analysis

Global Animal Genetics Market: Application Segment Analysis

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Global Animal Genetics Market Regional Outlook:

This market segmentation research is designed to provide complete market segmentation data in the following areas: Solution, Business, End-User, and Geography. Global demand for Animal Genetics is expected to see significant increase over the projected period. This study provides important market position statistics to industry leaders, which gives them information on current industry trends and future prospects. The Rowelto Associates uses business techniques and objective consumer knowAnimal Geneticsge to provide favorable outcomes. Projections and forecasts, as well as unfettered technical evaluations by sector, are possible if you do study. One data-driven research and quality recommendations for CXOs, CEOs, government officials, and investors is all wrapped up in this approach. With more insights, consumers will have greater motivation to solve issues.

The report provides insights on the following pointers:

1. Market Penetration: Provides comprehensive information on the market offered by the key players2. Market Development: Provides in-depth information about lucrative emerging markets and analyze penetration across mature segments of the markets3. Market Diversification: Provides detailed information about new product launches, untapped geographies, recent developments, and investments4. Competitive Assessment & Intelligence: Provides an exhaustive assessment of market shares, strategies, products, certification, regulatory approvals, patent landscape, and manufacturing capabilities of the leading players5. Product Development & Innovation: Provides intelligent insights on future technologies, R&D activities, and breakthrough product developments

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Animal Genetics Market Incredible Possibilities, Growth With Industry Study, Detailed Analysis And Forecast To 2029 Blackswan Real Estate - Blackswan...