Tumour lineage shapes BRCA-mediated phenotypes Academic Article uri icon

Overview

MeSH Major

  • DNA, Neoplasm
  • Germ-Line Mutation
  • Neoplasms

abstract

  • © 2019, The Author(s), under exclusive licence to Springer Nature Limited. 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.

authors

publication date

  • July 25, 2019

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/s41586-019-1382-1

PubMed ID

  • 31292550

Additional Document Info

start page

  • 576

end page

  • 579

volume

  • 571

number

  • 7766