Open AccessThe context-specific role of germline pathogenicity in tumorigenesis
Author(s) -
Preethi Srinivasan,
Chaitanya Bandlamudi,
Philip Jonsson,
Yelena Kemel,
Shweta S. Chavan,
Allison L. Richards,
A. Penson,
Craig M. Bielski,
Christopher J. Fong,
Aijazuddin Syed,
Gowtham Jayakumaran,
Meera Prasad,
Jason Hwee,
S. Onur Sumer,
Ino de Bruijn,
Xiang Li,
Jianjiong Gao,
Nikolaus Schultz,
Roy Cambria,
Jesse Galle,
Semanti Mukherjee,
Joseph Vijai,
Karen A. Cadoo,
Maria I. Carlo,
Michael F. Walsh,
Diana Mandelker,
Ozge CeyhanBirsoy,
Jinru Shia,
Ahmet Zehir,
Marc Ladanyi,
David M. Hyman,
Liying Zhang,
Kenneth Offit,
Mark E. Robson,
David B. Solit,
Zsofia K. Stadler,
Michael F. Berger,
Barry S. Taylor
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-021-00949-1
Subject(s) - germline , penetrance , biology , carcinogenesis , genetics , germline mutation , cancer , allele , somatic cell , context (archaeology) , gene , cancer research , phenotype , mutation , paleontology
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.