biostudies-literatureSrinivasan PFund for Innovation in Cancer InformaticsU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS1577-1585https://www.ebi.ac.uk/biostudies/studies/S-EPMC8957388biostudies-literatureUnknown53(11)Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetranceNature geneticsThe context-specific role of germline pathogenicity in tumorigenesis.PMC8957388R25 CA233208P30 CA008748R01 CA227534Vijai JBandlamudi CRichards ALJonsson PFong CLadanyi MPrasad MGao JZhang LOffit KPenson AVGalle JWalsh MFSchultz NSrinivasan PSumer SOBerger MFStadler ZKHwee Jde Bruijn ICeyhan-Birsoy OMandelker DJayakumaran GBielski CMCadoo KAKemel YHyman DMLi XZehir ARobson MEMukherjee STaylor BSShia JSyed AChavan SSCambria RCarlo MISolit DBfalseThe context-specific role of germline pathogenicity in tumorigenesis.Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance2021-01-01T00:00:00Z2021 Nov2025-04-22T01:41:42.729Z2025-02-19T00:29:15.794ZS-EPMC89573883474116210.1038/s41588-021-00949-1