Τίτλος:
Case–control analysis identifies shared properties of rare germline variation in cancer predisposing genes
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 < 0.1), while ultra-rare missense variants were significantly overrepresented in cases only in constrained 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. © 2019, European Society of Human Genetics.
Συγγραφείς:
Artomov, M.
Joseph, V.
Tiao, G.
Thomas, T.
Schrader, K.
Klein, R.J.
Kiezun, A.
Gupta, N.
Margolin, L.
Stratigos, A.J.
Kim, I.
Shannon, K.
Ellisen, L.W.
Haber, D.
Getz, G.
Tsao, H.
Lipkin, S.M.
Altshuler, D.
Offit, K.
Daly, M.J.
Περιοδικό:
European Journal of Human Genetics: EJHG
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
DNA; tumor suppressor protein; DNA, allele; Article; breast cancer; cancer risk; cancer susceptibility; case control study; cohort analysis; colon cancer; cutaneous melanoma; disease burden; early cancer; eye melanoma; family history; gene frequency; genetic predisposition; genetic risk; genetic screening; genetic variation; germline mutation; hospital based case control study; human; Li-Fraumeni syndrome; major clinical study; malignant neoplasm; phenotype; priority journal; skin cancer; genetics; germline mutation; neoplasm, Case-Control Studies; DNA; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Neoplasms
DOI:
10.1038/s41431-019-0346-0
