The context-specific role of germline pathogenicity in tumorigenesis

被引：66

作者：

Srinivasan, Preethi ^{[1
,8
]}

Bandlamudi, Chaitanya ^{[1
,2
]}

Jonsson, Philip ^{[2
]}

Kemel, Yelena ^{[3
]}

Chavan, Shweta S. ^{[2
]}

Richards, Allison L. ^{[2
]}

Penson, Alexander, V ^{[4
,5
]}

Bielski, Craig M. ^{[4
,5
]}

Fong, Christopher ^{[2
,5
]}

Syed, Aijazuddin ^{[1
]}

Jayakumaran, Gowtham ^{[1
]}

Prasad, Meera ^{[1
]}

Hwee, Jason ^{[1
]}

Sumer, Selcuk Onur ^{[2
]}

de Bruijn, Ino ^{[2
]}

Li, Xiang ^{[2
]}

Gao, JianJiong ^{[2
,5
]}

Schultz, Nikolaus ^{[2
,4
,5
]}

Cambria, Roy ^{[6
]}

Galle, Jesse ^{[6
]}

Mukherjee, Semanti ^{[3
,7
]}

Vijai, Joseph ^{[3
,7
]}

Cadoo, Karen A. ^{[3
,7
]}

Carlo, Maria, I ^{[3
,7
]}

Walsh, Michael F. ^{[3
,7
]}

Mandelker, Diana ^{[1
]}

Ceyhan-Birsoy, Ozge ^{[1
]}

Shia, Jinru ^{[1
]}

Zehir, Ahmet ^{[1
]}

Ladanyi, Marc ^{[1
,4
]}

Hyman, David M. ^{[7
,9
]}

Zhang, Liying ^{[1
,10
]}

Offit, Kenneth ^{[3
,7
]}

Robson, Mark E. ^{[3
,7
]}

Solit, David B. ^{[2
,4
,7
]}

Stadler, Zsofia K. ^{[3
,7
]}

Berger, Michael F. ^{[1
,2
,4
]}

Taylor, Barry S. ^{[2
,4
,5
,9
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Robert & Kate Niehaus Ctr Inherited Canc Genom, 1275 York Ave, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Res & Technol Management, 1275 York Ave, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[8] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA

[9] Loxo Oncol, Stamford, CT USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

来源：

NATURE GENETICS | 2021年 / 53卷 / 11期

基金：

美国国家卫生研究院;

关键词：

MUTATION DETECTION; CANCER; HEREDITARY; REPAIR; TUMORS; GENES; DNA; DEFICIENCY; LANDSCAPE; NEOPLASIA;

D O I：

10.1038/s41588-021-00949-1

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

A study of 17,152 patients with cancer identified pathogenic germline variants in cancer predisposition genes. Although tumors showed biallelic inactivation for high-penetrance genes, this was not the case in most patients with pathogenic variants in low-penetrance genes, suggesting alternative routes to 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-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.

引用

页码：1577 / +

页数：25

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