Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore
Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown sig...
| Үндсэн зохиолчид: | , , , , , , , , , , , , , , , , |
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| Бусад зохиолчид: | |
| Формат: | Journal Article |
| Хэл сонгох: | English |
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2021
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| Нөхцлүүд: | |
| Онлайн хандалт: | https://hdl.handle.net/10356/154510 |
| _version_ | 1826127421306306560 |
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| author | Shaw, Tarryn Chan, Sock Hoai Teo, Jing Xian Chong, Siao Ting Li, Shao-Tzu Courtney, Eliza Ishak, Diana Sankar, Haresh Ang, Zoe Li Ting Chiang, Jianbang Loh, Marie Zhou, Li Lee, Soo Chin Yeh, Hui-Yuan Kolinjivadi, Arun Mouli Lim, Weng Khong Ngeow, Joanne |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Shaw, Tarryn Chan, Sock Hoai Teo, Jing Xian Chong, Siao Ting Li, Shao-Tzu Courtney, Eliza Ishak, Diana Sankar, Haresh Ang, Zoe Li Ting Chiang, Jianbang Loh, Marie Zhou, Li Lee, Soo Chin Yeh, Hui-Yuan Kolinjivadi, Arun Mouli Lim, Weng Khong Ngeow, Joanne |
| author_sort | Shaw, Tarryn |
| collection | NTU |
| description | Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 bc using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic. |
| first_indexed | 2024-10-01T07:08:37Z |
| format | Journal Article |
| id | ntu-10356/154510 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:08:37Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1545102021-12-23T08:46:44Z Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore Shaw, Tarryn Chan, Sock Hoai Teo, Jing Xian Chong, Siao Ting Li, Shao-Tzu Courtney, Eliza Ishak, Diana Sankar, Haresh Ang, Zoe Li Ting Chiang, Jianbang Loh, Marie Zhou, Li Lee, Soo Chin Yeh, Hui-Yuan Kolinjivadi, Arun Mouli Lim, Weng Khong Ngeow, Joanne Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Asian Hereditary Identification of ancestry-specific pathogenic variants is imperative for diagnostic, treatment, management and prevention strategies, and to understand penetrance/modifiers on risk. Our study aimed to determine the clinical significance of a recurrent BRCA1 c.442-22_442-13del variant of unknown significance identified among 13 carriers from six Chinese families, all with a significant history of breast and/or ovarian cancer. We further aimed to establish whether this was due to a founder effect and explore its origins. Haplotype analysis, using nine microsatellite markers encompassing 2.5 megabase pairs around the BRCA1 locus, identified a common haploblock specific to the variant carriers, confirming a founder effect. Variant age was estimated to date back 77.9 generations to 69 bc using the Gamma approach. On principal component analysis using single nucleotide polymorphisms merged with 1000 Genomes dataset, variant carriers were observed to overlap predominantly with the southern Han Chinese population. To determine pathogenicity of the variant, we assessed the functional effect on RAD51 foci formation as well as replication fork stability upon induction of DNA damage and observed an impaired DNA repair response associated with the variant. In summary, we identified an ancient Chinese founder mutation dating back 77.9 generations, possibly common among individuals of southern Han Chinese descent. Using evidence from phenotypic/family history studies, segregation analysis and functional characterization, the BRCA1 variant was reclassified from uncertain significance to pathogenic. We express our gratitude to the Lee foundation for their generousdonations to the Lee Kong Chian NCCS Cancer Genetics Service(LKCNCCS) fund that helped subsidize the cost of testing for many ofour patients and make this study possible. 2021-12-23T08:46:44Z 2021-12-23T08:46:44Z 2021 Journal Article Shaw, T., Chan, S. H., Teo, J. X., Chong, S. T., Li, S., Courtney, E., Ishak, D., Sankar, H., Ang, Z. L. T., Chiang, J., Loh, M., Zhou, L., Lee, S. C., Yeh, H., Kolinjivadi, A. M., Lim, W. K. & Ngeow, J. (2021). Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore. International Journal of Cancer, 148(3), 637-645-645. https://dx.doi.org/10.1002/ijc.33241 0020-7136 https://hdl.handle.net/10356/154510 10.1002/ijc.33241 32745242 2-s2.0-85089688331 3 148 637-645 645 en International Journal of Cancer ©2020 Union for International Cancer Control. All rights reserved. |
| spellingShingle | Science::Medicine Asian Hereditary Shaw, Tarryn Chan, Sock Hoai Teo, Jing Xian Chong, Siao Ting Li, Shao-Tzu Courtney, Eliza Ishak, Diana Sankar, Haresh Ang, Zoe Li Ting Chiang, Jianbang Loh, Marie Zhou, Li Lee, Soo Chin Yeh, Hui-Yuan Kolinjivadi, Arun Mouli Lim, Weng Khong Ngeow, Joanne Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title | Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title_full | Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title_fullStr | Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title_full_unstemmed | Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title_short | Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore |
| title_sort | investigation into the origins of an ancient brca1 founder mutation identified among chinese families in singapore |
| topic | Science::Medicine Asian Hereditary |
| url | https://hdl.handle.net/10356/154510 |
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