Ancestry-specific predisposing germline variants in cancer

Background Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of diverse populations. Methods We conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas. Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups. We also identified the predisposition-associated two-hit events and gene expression effects in tumors. Results Genetic ancestry analysis classified the cohort of 9899 cancer cases into individuals of primarily European ( N  = 8184, 82.7%), African ( N  = 966, 9.8%), East Asian ( N  = 649, 6.6%), South Asian ( N  = 48, 0.5%), Native/Latin American ( N  = 41, 0.4%), and admixed ( N  = 11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1–275.6]; FDR = 0.002) previously identified in Europeans, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma (OR = 8.5 [95% CI, 1.5–47.4]; FDR = 0.045). In the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR = 12.8 [95% CI, 1.8–90.8]; FDR = 0.038). Rare variant burden analysis further identified 7 suggestive associations in African ancestry individuals previously described in European ancestry, including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH . Conclusions While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Studies using larger cohorts of diverse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies.

[1]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[2]  C. Pratt,et al.  St. Jude Children's Research Hospital. , 1997, Pediatric hematology and oncology.

[3]  H. Mefford,et al.  BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. , 1997, American journal of human genetics.

[4]  S. Seal,et al.  Brave new now , 2013, Nature Genetics.

[5]  M. King,et al.  Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. , 1998, JAMA.

[6]  A. Knudson,et al.  Two genetic hits (more or less) to cancer , 2001, Nature Reviews Cancer.

[7]  P. Choyke,et al.  Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer , 2005, Journal of Medical Genetics.

[8]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[9]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[10]  Nazneen Rahman,et al.  Genetic predisposition to breast cancer: past, present, and future. , 2008, Annual review of genomics and human genetics.

[11]  David H. Alexander,et al.  Fast model-based estimation of ancestry in unrelated individuals. , 2009, Genome research.

[12]  Scott M. Williams,et al.  The Genetic Structure and History of Africans and African Americans , 2009, Science.

[13]  Kai Ye,et al.  Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads , 2009, Bioinform..

[14]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[15]  A. Kurian.  BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications , 2010, Current opinion in obstetrics & gynecology.

[16]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[17]  W. Krzyzosiak,et al.  Sequence-non-specific effects of RNA interference triggers and microRNA regulators , 2009, Nucleic acids research.

[18]  S. Majumdar,et al.  Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma , 2010, Pediatric blood & cancer.

[19]  Derek Y. Chiang,et al.  MapSplice: Accurate mapping of RNA-seq reads for splice junction discovery , 2010, Nucleic acids research.

[20]  J. Lupski,et al.  Clan Genomics and the Complex Architecture of Human Disease , 2011, Cell.

[21]  Wei Pan,et al.  Comparison of statistical tests for disease association with rare variants , 2011, Genetic epidemiology.

[22]  Xihong Lin,et al.  Rare-variant association testing for sequencing data with the sequence kernel association test. , 2011, American journal of human genetics.

[23]  Christopher A. Miller,et al.  VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. , 2012, Genome research.

[24]  O. Olopade,et al.  High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients , 2012, International journal of cancer.

[25]  W. Han,et al.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls. , 2013, Human molecular genetics.

[26]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[27]  William Wheeler,et al.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer , 2014, Nature Genetics.

[28]  T. Walsh,et al.  Inherited predisposition to breast cancer among African American women , 2014, Breast Cancer Research and Treatment.

[29]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[30]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[31]  A. Nowacki,et al.  Association of specific PTEN/10q haplotypes with endometrial cancer phenotypes in African-American and European American women. , 2015, Gynecologic oncology.

[32]  Li Ding,et al.  Patterns and functional implications of rare germline variants across 12 cancer types , 2015, Nature Communications.

[33]  M. Milowsky,et al.  Intrinsic Genomic Differences Between African American and White Patients With Clear Cell Renal Cell Carcinoma. , 2016, JAMA oncology.

[34]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[35]  Levi Waldron,et al.  Racial/Ethnic Disparities in Genomic Sequencing. , 2016, JAMA oncology.

[36]  Mary Brophy,et al.  Million Veteran Program: A mega-biobank to study genetic influences on health and disease. , 2016, Journal of clinical epidemiology.

[37]  Lara E Sucheston-Campbell,et al.  Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer. , 2016, Human molecular genetics.

[38]  Trey Ideker,et al.  Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer. , 2017, Cancer discovery.

[39]  K. Cooney,et al.  Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. , 2017, European urology.

[40]  Robert Huether,et al.  Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer , 2017, JAMA oncology.

[41]  Quan Li,et al.  InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines. , 2017, American journal of human genetics.

[42]  Feng-Chi Chen,et al.  NMD Classifier: A reliable and systematic classification tool for nonsense-mediated decay events , 2017, PloS one.

[43]  Gunnar Rätsch,et al.  Germline determinants of the somatic mutation landscape in 2,642 cancer genomes , 2017, bioRxiv.

[44]  Peter W. Laird,et al.  Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas , 2017, JAMA oncology.

[45]  F. Supek,et al.  Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits , 2018, Nature Communications.

[46]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[47]  Li Ding,et al.  Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics , 2018, Cell.

[48]  Steven J. M. Jones,et al.  Pathogenic Germline Variants in 10,389 Adult Cancers. , 2018, Cell.

[49]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[50]  K. Offit,et al.  Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes , 2018, Human mutation.

[51]  N. Risch,et al.  The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations. , 2018, American journal of human genetics.

[52]  Clement Adebamowo,et al.  A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. , 2018, Cancer cell.

[53]  Heidi L. Rehm,et al.  Harmonizing Clinical Sequencing And Interpretation For The Emerge III Network , 2018, bioRxiv.

[54]  T. Rebbeck,et al.  Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. , 2018, Cancer cell.

[55]  James M Ford,et al.  Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk , 2017, Genetics in Medicine.

[56]  C. Vachon,et al.  Common Genetic Variation and Breast Cancer Risk—Past, Present, and Future , 2018, Cancer Epidemiology, Biomarkers & Prevention.

[57]  K. Cooney,et al.  Rare germline mutations in African American men diagnosed with early‐onset prostate cancer , 2018, The Prostate.

[58]  E. Green,et al.  Prioritizing diversity in human genomics research , 2017, Nature Reviews Genetics.

[59]  R. Klein,et al.  Rare, Pathogenic Germline Variants in Fanconi Anemia Genes Increase Risk for Squamous Lung Cancer , 2018, Clinical Cancer Research.

[60]  A. Nugent,et al.  Reporting of race in genome and exome sequencing studies of cancer: a scoping review of the literature , 2019, Genetics in Medicine.

[61]  E. Kenny,et al.  Personalized Medicine and the Power of Electronic Health Records , 2019, Cell.

[62]  Ryan L. Collins,et al.  The mutational constraint spectrum quantified from variation in 141,456 humans , 2020, Nature.

[63]  Robert C. Green,et al.  Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. , 2019, American journal of human genetics.

[64]  Li Ding,et al.  CharGer: clinical Characterization of Germline variants , 2018, Bioinform..

[65]  Ryan L. Collins,et al.  Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes , 2019, bioRxiv.

[66]  A. Toland,et al.  Germline Variants Impact Somatic Events during Tumorigenesis. , 2019, Trends in genetics : TIG.

[67]  Sohini Ramachandran,et al.  Germline Features Associated with Immune Infiltration in Solid Tumors. , 2020, Cell reports.

[68]  Jeffrey S. Damrauer,et al.  Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer , 2020, Cancer Cell.

[69]  The Icgctcga Pan-Cancer Analysis of Whole Genomes Consortium.  Pan-cancer analysis of whole genomes , 2020 .

[70]  Steven J. M. Jones,et al.  Pan-cancer analysis of whole genomes , 2020, Nature.