Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers
Name
eaay2611.full.pdf
Description
Published version
Size
6.43 MB
Format
Adobe PDF
Checksum (MD5)
5fd28443b34a9d798143cab01f7b9584
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
Date Issued
2020
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Version
Final published version
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Picower Institute for Learning and Memory
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/SCIADV.AAY2611
