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Tumour lineage shapes BRCA-mediated phenotypes.
- Source :
-
Nature [Nature] 2019 Jul; Vol. 571 (7766), pp. 576-579. Date of Electronic Publication: 2019 Jul 10. - Publication Year :
- 2019
-
Abstract
- Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers <superscript>1-3</superscript> , and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients <superscript>4,5</superscript> . These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours <superscript>6,7</superscript> . Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination <superscript>8-13</superscript> , and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP) <superscript>14,15</superscript> . 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.
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 571
- Issue :
- 7766
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 31292550
- Full Text :
- https://doi.org/10.1038/s41586-019-1382-1