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Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

ABSTRACT: Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI??0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.

SUBMITTER: Artomov M

PROVIDER: S-EPMC6461796 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

Artomov Mykyta M Joseph Vijai V Tiao Grace G Thomas Tinu T Schrader Kasmintan K Klein Robert J RJ Kiezun Adam A Gupta Namrata N Margolin Lauren L Stratigos Alexander J AJ Kim Ivana I Shannon Kristen K Ellisen Leif W LW Haber Daniel D Getz Gad G Tsao Hensin H Lipkin Steven M SM Altshuler David D Offit Kenneth K Daly Mark J MJ

European journal of human genetics : EJHG 20190204 5

Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different ...[more]

PMID: 30718883

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Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

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Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

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