Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers
Author(s)
Karaayvaz-Yildirim, Mihriban; Silberman, Rebecca E; Langenbucher, Adam; Saladi, Srinivas Vinod; Ross, Kenneth N; Zarcaro, Elena; Desmond, Andrea; Yildirim, Murat; Vivekanandan, Varunika; Ravichandran, Hiranmayi; Mylavagnanam, Ravindra; Specht, Michelle C; Ramaswamy, Sridhar; Lawrence, Michael; Amon, Angelika; Ellisen, Leif W; ... Show more Show less
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Copyright © 2020 The Authors, some rights reserved. Women harboring heterozygous germline mutations of BRCA2 have a 50 to 80% risk of developing breast cancer, yet the 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, which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ 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 BRCA2 allele. Collectively, our findings suggest that BRCA2 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.
Date issued
2020Department
Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Howard Hughes Medical Institute; Picower Institute for Learning and MemoryJournal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)