Women harboring heterozygous germline mutations of have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in -associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of carrier ( ) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary 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 allele. Collectively, our findings suggest that 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.
