The context-specific role of germline pathogenicity in tumorigenesis
| Autor: | Marc Ladanyi, Gowtham Jayakumaran, Karen Cadoo, Ahmet Zehir, Philip Jonsson, Xiang Li, Jason Hwee, Meera Prasad, Michael Walsh, Jinru Shia, Allison Richards, Alexander V Penson, Aijazuddin Syed, Joseph Vijai, Roy Cambria, Michael F. Berger, Barry S. Taylor, Mark E. Robson, Semanti Mukherjee, Chaitanya Bandlamudi, Jianjiong Gao, Christopher J. Fong, Ozge Ceyhan-Birsoy, Maria I. Carlo, Liying Zhang, David M. Hyman, Preethi Srinivasan, Ino de Bruijn, Diana Mandelker, Jesse Galle, Selcuk Onur Sumer, Craig M. Bielski, Kenneth Offit, Shweta S. Chavan, Nikolaus Schultz, Yelena Kemel, David B. Solit, Zsofia K. Stadler |
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| Rok vydání: | 2021 |
| Předmět: |
Heterozygote
DNA Copy Number Variations Carcinogenesis Somatic cell Biology medicine.disease_cause DNA Mismatch Repair Medical and Health Sciences Germline Rare Diseases Clinical Research Neoplasms Genetics medicine Humans 2.1 Biological and endogenous factors Genetic Predisposition to Disease Aetiology Allele Gene Germ-Line Mutation Cancer Human Genome Biological Sciences medicine.disease Phenotype Penetrance Developmental Biology |
| Zdroj: | Nature genetics, vol 53, iss 11 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/s41588-021-00949-1 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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