Tumour lineage shapes BRCA-mediated phenotypes.

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.

journal_name

Nature

journal_title

Nature

authors

Jonsson P,Bandlamudi C,Cheng ML,Srinivasan P,Chavan SS,Friedman ND,Rosen EY,Richards AL,Bouvier N,Selcuklu SD,Bielski CM,Abida W,Mandelker D,Birsoy O,Zhang L,Zehir A,Donoghue MTA,Baselga J,Offit K,Scher HI,O'Reill

doi

10.1038/s41586-019-1382-1

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

576-579

issue

7766

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-019-1382-1

journal_volume

571

pub_type

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