Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers
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 cel...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2021
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| Online Access: | https://hdl.handle.net/1721.1/136226 |
| _version_ | 1811087082071785472 |
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| author | 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 |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT 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 |
| author_sort | Karaayvaz-Yildirim, Mihriban |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:39:30Z |
| format | Article |
| id | mit-1721.1/136226 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:39:30Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1362262023-11-07T19:17:53Z Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers 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 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 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. 2021-10-27T20:34:21Z 2021-10-27T20:34:21Z 2020 2021-07-13T17:20:40Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136226 en 10.1126/SCIADV.AAY2611 Science Advances Creative Commons Attribution NonCommercial License 4.0 https://creativecommons.org/licenses/by-nc/4.0/ application/pdf American Association for the Advancement of Science (AAAS) Science Advances |
| spellingShingle | 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 Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title | Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title_full | Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title_fullStr | Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title_full_unstemmed | Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title_short | Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers |
| title_sort | aneuploidy and a deregulated dna damage response suggest haploinsufficiency in breast tissues of brca2 mutation carriers |
| url | https://hdl.handle.net/1721.1/136226 |
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