Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers
| Autor: | Ravindra Mylavagnanam, Sridhar Ramaswamy, Elena Zarcaro, Srinivas Vinod Saladi, Andrea Desmond, Murat Yildirim, Varunika Vivekanandan, Michael S. Lawrence, Kenneth N. Ross, Mihriban Karaayvaz-Yildirim, Rebecca E. Silberman, Adam Langenbucher, Leif W. Ellisen, Angelika Amon, Michelle C. Specht, Hiranmayi Ravichandran |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Multidisciplinary DNA damage Aneuploidy Biology medicine.disease medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Germline mutation Breast cancer 030220 oncology & carcinogenesis medicine Cancer research Copy-number variation Allele skin and connective tissue diseases Carcinogenesis Haploinsufficiency 030304 developmental biology |
| Zdroj: | Science Advances. 6 |
| ISSN: | 2375-2548 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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