Germline Variants In Cancer Research Articles

Abstract 2041: Research strategies for rare germline variants and cancer study

Abstract Exploration of rare germline variants in cancer is the fields of ongoing research. So, we would like to suggest several considerations for the rare pathogenic germline variants studies. We confirmed the pathogenicity of each variant using ClinVar (https://www.ncbi.nlm.nih.gov/clinvar). In addition, we utilized in silico prediction tools such as Polyphen and SIFT. Even for the same variant, the report of the variant may vary depending on the database used. We conducted rare germline variants screening using ICGC (International Cancer Genome Consortium) PCAWG (Pan-Cancer Analysis of Whole Genomes) data. we filtered allele frequencies using the gnomAD (v2.1.1) exome database. We utilized several ClinVar versions to check the clinical significance of germline variants. Next, we have investigated some in silico tools that predict ClinVar pathogenic and benign variants well. We observed inconsistent variant reports across versions of ClinVar. Although the information on variants may change over time, there have been inconsistent changes in the clinical significance of variants reported as P (Pathogenic) or LP (Likely pathogenic). The clinical significance of the variants reported in the previous version was P or LP, but those in the updated version were changed to “Conflicting interpretations of pathogenicity”. It was confirmed that the variant report changes when at least one “Uncertain Significance” review is added. Among various prediction tools, we found that the predictive power of a tool called “MetaRNN” was useful. Compared with several tools, we confirmed that MetaRNN’s AUC (Area Under the ROC Curve) value was 0.985, which is the best performance. But, it is not enough to judge the pathogenicity of a variant only by the prediction result of the tool. And, prediction tools are also known to be more efficient in predicting missense variants than others. Therefore, it is necessary to examine the pathogenicity of germline variants using both the prediction tool and the clinical significance of ClinVar. In summary, for rare germline variants in cancer studies, it is necessary to observe variants compared to the previous versions of ClinVar. Moreover, if prediction tools are appropriately used, researchers will increase the possibility of finding a variant or gene with more crucial clinical significance to reveal the association between the rare germline variants and cancer development. Citation Format: Seokhyeon Kim, Youngil Koh, Sung-Soo Yoon. Research strategies for rare germline variants and cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2041.

An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.

Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.

138P Prevalence and characteristics of lung cancer in families harboring pathogenic germline variants in cancer predisposing genes

Emerging evidence indicates that lung cancer can be associated with certain hereditary cancer syndromes caused by pathogenic germline variants (PGVs). However, this population is not currently studied in Genetic Counseling Units (GCU) and their role in patients (pts) with lung cancer remains unknown. We aim to describe the prevalence and characteristics of lung cancer cases in families harboring PGVs in cancer predisposing genes.

A decade of RAD51C and RAD51D germline variants in cancer

Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.

The first comprehensive database of germline pathogenic variants in East Asian cancer patients

Pathogenic germline variants in cancer-associated genes are risk factors for cancer predisposition. However, systematic mining and summarizing of cancer pathogenic or likely pathogenic variants has not been performed for people of East Asian descent. This study aimed to investigate publicly available data to identify germline variants in East Asian cancer cohorts and compare them to variants in Caucasian cancer cohorts. Based on the data we retrieved, we built a comprehensive database, named COGVIC (Catalog of Germline Variants in Cancer). A total of 233 variants in the East Asian population were identified. The majority (87%) of genes with cancer-associated variants were not shared between the East Asian and Caucasian cohorts. This included pathogenic variants in BRCA2. Our study summarized the prevalence of germline variants in East Asian cancer cohorts and provides an easy-to-use online tool to explore germline mutations related to cancer susceptibility.Database URL http://www.cogvic.vip/

Genomic Profiling of Lung Adenocarcinoma in Never-Smokers.

Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.

Inherited MC1R variants in patients with melanoma are associated with better survival in women.

SummaryBackgroundWomen have a better melanoma prognosis, and fairer skin/hair colour. The presence of inherited MC1R variants has been associated with a better melanoma prognosis, but its interaction with sex is unknown.ObjectivesTo evaluate the relationship between germline MC1R status and survival, and determine any association with sex.MethodsThis was a cohort study including 1341 patients with melanoma from the Melanoma Unit of the Hospital Clinic of Barcelona, between January 1996 and April 2018. We examined known sex‐related prognosis factors as they relate to features of melanoma and evaluated the sex‐specific role of MC1R in overall and melanoma‐specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox logistic regression.ResultsMen showed lower overall survival than women (P < 0·001) and the presence of inherited MC1R variants was not associated with better survival in our cohort. However, in women the presence of MC1R variants was associated with better overall survival in the multivariate analysis [HR 0·57, 95% confidence interval (CI) 0·38–0·85; P = 0·006] but not in men [HR 1·26, 95% CI 0·89–1·79; P = 0·185 (P‐value for interaction 0·004)]. Analysis performed for melanoma‐specific survival showed the same level of significance.ConclusionsInherited MC1R variants are associated with improved overall survival in women with melanoma but not in men. Intrinsic sex‐dependent features can modify the role of specific genes in melanoma prognosis. We believe that survival studies of patients with melanoma should include analysis by sex and MC1R genotype. What's already known about this topic? Inherited MC1R variants have been associated with a better melanoma prognosis, but their interaction with sex is unknown. What does this study add? MC1R variants are related to better overall survival and melanoma‐specific survival in women but not in men. What is the translational message? These differences between the sexes could imply future changes in melanoma follow‐up and treatment strategies.This provides a basis for understanding the interaction between sex‐related genes and germline variants in cancer.

Prevalence of germline variants in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

Abstract 5359: Regulatory germline variants in 10,389 adult cancers

Abstract Previous studies of rare germline variants in cancer has largely been limited to the coding regions of known predisposition genes. The TCGA PanCanAtlas Germline Working Group is analyzing germline predisposing variants of 10,389 cases in 33 cancer types. We deployed more than 121,000 virtual machines running for over 600,000 hours on the ISB Cancer Genome Cloud to conduct massively parallel variant calling and analyses, and the resulting data are shared with scientists across institutions worldwide. Carriers of the functional regulatory variants add on to the 8.9% of cases carrying known pathogenic variants. Burden analyses reveal enrichment of rare variants in the 3'UTR region of NHP2 and POLH. Further, we observed variants aggregating in conserved regions of selected microRNA families that are also affected by somatic mutations, including mir-17 and mir-29. We nominate regulatory variants by using GWAVA and FunSeq2 corroborated with their enrichment in cancer. The prioritized variants are then further evaluated by further co-occurrence of two-hit events and expression changes in their respective tumor samples. Finally, we examine ancestries, familial history and age at onset for carriers of these variants. Overall, we aim to discover and establish the role of regulatory germline variants in oncogenesis. Citation Format: Kuan-lin Huang, Amila Weerasinghe, Yige Wu, Wen-wei Liang, R. Jay Mashl, Sheila Reynolds, Kathleen E. Houlahan, Ninad Oak, The Cancer Genome Atlas, Alexander J. Lazar, Michael C. Wendel, Ekta Khurana, Sharon Plon, Feng Chen, Mark Gerstein, Ilya Shmulevich, Li Ding. Regulatory germline variants in 10,389 adult cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5359.

Expanding the spectrum of germline variants in cancer.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.

Abstract 1939: Discovery and proteogenomic investigation of genetic variants in human cancers

Abstract A significant fraction of cancers have a heritable component, and require an interplay between somatic and germline variants. Common and rare germline variants have been investigated by previous GWAS and family based studies. However, a comprehensive analysis of both somatic and germline variants in cancer using high throughput sequencing data to discover genetic variants of functional relevance is lacking. Herein, we investigated the potential role of somatic and germline variants from over 20 major cancer types from large-scale studies such as TCGA and ICGC and discovered thousands of somatic and germline variants in cancer genomes. To link these genetic variants to cancer phenotypes, we analyzed the proteomics data in breast, ovarian and colorectal cancers generated by the Clinical Proteomic Tumour Analysis Consortium (CPTAC) using a PepScan pipeline that can detect whether a genomic variant is observed at the peptide level. The pipeline incorporated QUILTS to construct patient-specific protein database and MS-GF+ to identify peptide sequences in the database from MS spectra. Our analysis validated roughly 2% of non-synonymous genetic variants in peptides with matched spectra. We correlated the effect of genetic mutations on proteomic subtypes based on global protein expression levels. Additionally, we assessed the role of genetic variations in kinase genes using phosphoproteome profiles, and identified downstream markers that may be candidate targets for diagnosis or treatment. This analysis also helped us prioritize kinase variants that are likely functional candidates for experimental validation. In conclusion, the comprehensive study of genetic variants utilizing an integrated proteogenomic approach revealed genetic variants with potential functional impacts in cancer. Citation Format: Kuan-lin Huang, Jaiyin Wang, Song Cao, Mingchao Xie, Reyka Jayasinghe, Jie Ning, Michael McLellan, Michael Wendl, Adam Scott, Kimberly Johnson, Sherri Davies, David Fenyö, Reid Townsend, Feng Chen, Jeffrey Parvin, Matthew Ellis, Li Ding. Discovery and proteogenomic investigation of genetic variants in human cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1939. doi:10.1158/1538-7445.AM2015-1939