Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers
العنوان: | Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers |
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المؤلفون: | Michelle C. Specht, Murat Yildirim, Michael S. Lawrence, Mihriban Karaayvaz, Srinivas Vinod Saladi, Angelika Amon, Adam Langenbucher, Rebecca E. Silberman, Varunika Vivekanandan, Andrea Desmond, Leif W. Ellisen, Sridhar Ramaswamy, Kenneth N. Ross, Ravindra Mylavagnanam, Elena Zarcaro, Hiranmayi Ravichandran |
بيانات النشر: | Cold Spring Harbor Laboratory, 2019. |
سنة النشر: | 2019 |
مصطلحات موضوعية: | endocrine system diseases, DNA damage, Aneuploidy, Biology, medicine.disease, medicine.disease_cause, Phenotype, Breast cancer, Germline mutation, Cancer research, medicine, Copy-number variation, skin and connective tissue diseases, Haploinsufficiency, Carcinogenesis |
الوصف: | 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. We sought to reveal early steps in BRCA2-associated carcinogenesis through analysis of sorted cell populations from freshly-isolated, non-cancerous breast tissues among a cohort 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 and replication stress-induced DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment in human carrier tissues. These phenotypes are not associated with loss of wild-type BRCA2. Collectively, these findings provide evidence for BRCA2 haploinsufficiency and associated DNA damage in vivo that precede histologic abnormalities. These results provide unanticipated opportunities for new cancer risk assessment and prevention strategies in high-risk patients. |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7aca1536bb1e9698d683f92a1ea1e17 https://doi.org/10.1101/729301 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....b7aca1536bb1e9698d683f92a1ea1e17 |
قاعدة البيانات: | OpenAIRE |
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