Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers
Mihriban Karaayvaz, Rebecca E Silberman, Adam Langenbucher, Srinivas Vinod Saladi, Kenneth N Ross, Elena Zarcaro, Andrea Desmond, Murat Yildirim, Varunika Vivekanandan, Hiranmayi Ravichandran, Ravindra Mylavagnanam, Michelle C Specht, Sridhar Ramaswamy, Michael Lawrence, Angelika Amon, Leif W Ellisen
Women harboring heterozygous germline mutations of BRCA2 have a 50-80% risk of developing breast cancer, yet the early pathogenesis of these cancers is poorly understood. To reveal early steps in BRCA2-associated carcinogenesis we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations (CNVs), which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit spontaneous DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type BRCA2 allele. Collectively, our findings suggest that BRCA2 haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Employing such hallmarks of cancer predisposition will yield unanticipated opportunities for new risk assessment and prevention strategies in high-risk patients.