 Tumour lineage shapes BRCA-mediated phenotypesPhilip Jonsson,
Chaitanya Bandlamudi,
Michael L. Cheng,
Preethi Srinivasan,
Shweta S. Chavan,
Noah D. Friedman,
Ezra Y. Rosen,
Allison L. Richards,
Nancy Bouvier,
S. Duygu Selcuklu,
Craig M. Bielski,
Wassim Abida,
Diana Mandelker,
Ozge Birsoy,
Liying Zhang,
Ahmet Zehir,
Mark T. A. Donoghue,
José Baselga,
Kenneth Offit,
Howard I. Scher,
Eileen M. O’Reilly,
Zsofia K. Stadler,
Nikolaus Schultz,
Nicholas D. Socci,
Agnes Viale,
Marc Ladanyi,
Mark E. Robson,
David M. Hyman,
Michael F. Berger (),
David B. Solit () and
Barry S. Taylor ()
Nature, 2019, vol. 571, issue 7766, 576-579 Abstract: Abstract Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1–3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8–13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)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. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:571:y:2019:i:7766:d:10.1038_s41586-019-1382-1 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-019-1382-1 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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