1. Tumour lineage shapes BRCA-mediated phenotypes
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Jonsson, Philip, Bandlamudi, Chaitanya, Cheng, Michael L., Srinivasan, Preethi, Chavan, Shweta S., Friedman, Noah D., and Rosen, Ezra Y.
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Gene mutations -- Health aspects ,Tumors -- Genetic aspects -- Development and progression ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers.sup.1-3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients.sup.4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours.sup.6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination.sup.8-13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP).sup.14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral--a difference predominantly conditioned by tumour lineage--with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making. Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage., Author(s): Philip Jonsson [sup.1] [sup.2] [sup.3] , Chaitanya Bandlamudi [sup.1] , Michael L. Cheng [sup.4] [sup.7] , Preethi Srinivasan [sup.5] , Shweta S. Chavan [sup.1] , Noah D. Friedman [sup.2] [...]
- Published
- 2019
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