Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of <i>BRCA2</i> mutation carriers.

Abstract

Women harboring heterozygous germline mutations of <i>BRCA2</i> have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in <i>BRCA2</i>-associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of <i>BRCA2</i> mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of <i>BRCA2</i> carrier (<i>BRCA2^mut/+</i> ) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary <i>BRCA2^mut/+</i> breast epithelia exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses, and an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type <i>BRCA2</i> allele. Collectively, our findings suggest that <i>BRCA2</i> haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients.