Synapse - The context-specific role of germline pathogenicity in tumorigenesis

The context-specific role of germline pathogenicity in tumorigenesis Journal Article

Authors:	Srinivasan, P.; Bandlamudi, C.; Jonsson, P.; Kemel, Y.; Chavan, S. S.; Richards, A. L.; Penson, A. V.; Bielski, C. M.; Fong, C.; Syed, A.; Jayakumaran, G.; Prasad, M.; Hwee, J.; Sumer, S. O.; de Bruijn, I.; Li, X.; Gao, J. J.; Schultz, N.; Cambria, R.; Galle, J.; Mukherjee, S.; Vijai, J.; Cadoo, K. A.; Carlo, M. I.; Walsh, M. F.; Mandelker, D.; Ceyhan-Birsoy, O.; Shia, J.; Zehir, A.; Ladanyi, M.; Hyman, D. M.; Zhang, L.; Offit, K.; Robson, M. E.; Solit, D. B.; Stadler, Z. K.; Berger, M. F.; Taylor, B. S.
Article Title:	The context-specific role of germline pathogenicity in tumorigenesis
Abstract:	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-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords:	adult; controlled study; human cell; major clinical study; cancer patient; prospective study; phenotype; allele; genetic association; carcinogenesis; germ line; genetic susceptibility; pathogenicity; penetrance; zygosity; human; male; female; article
Journal Title:	Nature Genetics
Volume:	53
Issue:	11
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Date Published:	2021-11-01
Start Page:	1577
End Page:	1585
Language:	English
DOI:	10.1038/s41588-021-00949-1
PROVIDER:	scopus
PUBMED:	34741162
PMCID:	PMC8957388
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85118575600&doi=10.1038%2fs41588-021-00949-1&partnerID=40&md5=7fece9a30e4d05915aedc1e9578f4235
Notes:	Article -- Export Date: 1 December 2021 -- Source: Scopus