Integrating germline and somatic genetics to identify genes associated with lung cancer.
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ABSTRACT:
SUBMITTER: Pattee J
PROVIDER: S-EPMC7064390 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes. The GSVS then reviewed and analyzed available resources of relevant somatic data, and performed integrative germline variant curation exercises. The committee determined that somatic hotspots could be systematically integrated into moderate evidence of pathogenicity (PM1). Tumor RNA sequencing data showing altered splicing may be considered as strong evidence in support of germline pathogenicity (PVS1) and tumor phenotypic features such as mutational signatures be considered supporting evidence of pathogenicity (PP4). However, at present, somatic data such as focal loss of heterozygosity and mutations occurring on the alternative allele are not recommended to be systematically integrated, instead, incorporation of this type of data should take place under the advisement of multidisciplinary cancer center tumor-normal sequencing boards.
| S-EPMC6310222 | biostudies-literature
Project description:We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p?=?0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.
| S-EPMC6882827 | biostudies-literature
Project description:Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the USA. Advances in high-throughput genotyping and next generation sequencing technologies have enabled discovery of germline genetic susceptibility variants and somatic mutations acquired during tumor formation. Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic variation and their role in aggressive PCa remain largely unexplored. Here we investigated the possible oncogenic interactions and cooperation between genes containing germline variation from genome-wide association studies (GWAS) and genes containing somatic mutations from tumor genomes of 305 men with aggressive tumors and 52 control samples from The Cancer Genome Atlas (TCGA). Network and pathway analysis were performed to identify molecular networks and biological pathways enriched for germline and somatic mutations. The analysis revealed 90 functionally related genes containing both germline and somatic mutations. Transcriptome analysis revealed a 61-gene signature containing both germline and somatic mutations. Network analysis revealed molecular networks of functionally related genes and biological pathways including P53, STAT3, NKX3-1, KLK3, and Androgen receptor signaling pathways enriched for germline and somatic mutations. The results show that integrative analysis is a powerful approach to uncovering the possible oncogenic interactions and cooperation between germline and somatic mutations and understanding the broader biological context in which they operate in aggressive PCa.
| S-EPMC6441536 | biostudies-literature
Project description:Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.
| S-EPMC6466377 | biostudies-literature
Project description:IntroductionDatabases used for clinical interpretation in oncology rely on genetic data derived primarily from patients of European ancestry, leading to biases in cancer genetics research and clinical practice. One practical issue that arises in this context is the potential misclassification of multi-ancestral population variants as tumor-associated because they are not represented in reference genomes against which tumor sequencing data is aligned.MethodsTo systematically find misclassified variants, we compared somatic variants in census genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) V99 with multi-ancestral population variants from the Genome Aggregation Databases' Linkage Disequilibrium (GnomAD). By comparing genomic coordinates, reference, and alternate alleles, we could identify misclassified variants in genes associated with cancer.ResultsWe found 192 of 208 genes in COSMIC's cancer-associated census genes (92.31%) to be associated with variant misclassifications. Among the 1,906,732 variants in COSMIC, 6,957 variants (0.36%) aligned with normal population variants in GnomAD, concerning for misclassification. The African / African American ancestral population included the greatest number of misclassified variants and also had the greatest number of unique misclassified variants.ConclusionThe direct, systematic comparison of variants from COSMIC for co-occurrence in GnomAD supports a more accurate interpretation of tumor sequencing data and reduces bias related to genomic ancestry.
| S-EPMC10987807 | biostudies-literature
Project description:BackgroundAn important fraction (>/~10%) of men with high-risk, localized prostate cancer and metastatic prostate cancer carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. These can represent known or suspected autosomal dominant cancer predisposition syndromes. Growing evidence suggests that pathogenic variants in key genes involved in homologous recombination and mismatch DNA repair are important in prostate cancer initiation and/or the development of metastases.AimsHere we provide a comprehensive review regarding individual genes and available literature regarding risks for developing prostate cancer, and discuss current national guidelines for germline genetic testing in the prostate cancer population and treatment implications.ResultsThe association with prostate cancer risk and treatment implications is best understood for those with germline mutations of BRCA2, with emerging data supporting associations with ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN. Treatment implications in the metastatic castration resistant prostate cancer setting include rucaparib and olaparib, and pembrolizumab with potential clinical trial opportunities in earlier disease settings.DiscussionThe data summarized in this review has led to the expansion of national guidelines for germline genetic testing in prostate cancer. We review these guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations with attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.
| S-EPMC9255908 | biostudies-literature
Project description:BackgroundProstate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the United States. High-throughput genotyping has enabled discovery of germline genetic susceptibility variants (herein referred to as germline mutations) associated with an increased risk of developing PCa. However, germline mutation information has not been leveraged and integrated with information on acquired somatic mutations to link genetic susceptibility to tumorigenesis. The objective of this exploratory study was to address this knowledge gap.MethodsGermline mutations and associated gene information were derived from genome-wide association studies (GWAS) reports. Somatic mutation and gene expression data were derived from 495 tumors and 52 normal control samples obtained from The Cancer Genome Atlas (TCGA). We integrated germline and somatic mutation information using gene expression data. We performed enrichment analysis to discover molecular networks and biological pathways enriched for germline and somatic mutations.ResultsWe discovered a signature of 124 genes containing both germline and somatic mutations. Enrichment analysis revealed molecular networks and biological pathways enriched for germline and somatic mutations, including, the PDGF, P53, MYC, IGF-1, PTEN and Androgen receptor signaling pathways.ConclusionIntegrative genomic analysis links genetic susceptibility to tumorigenesis in PCa and establishes putative functional bridges between the germline and somatic variation, and the biological pathways they control.
| S-EPMC6417124 | biostudies-literature
Project description:BackgroundGermline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants.MethodsTo identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided.ResultsThe GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors.ConclusionsThis study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
| S-EPMC9360465 | biostudies-literature
Project description:ObjectivesMAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE.MethodsWe enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays.ResultsWe identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation.ConclusionsMultiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.
| S-EPMC8762023 | biostudies-literature
Project description:Genome-wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common-enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12-0.55, P = 3.93 × 10-4 ). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.
| S-EPMC6089170 | biostudies-literature