Germline breast cancer susceptibility genes, tumor characteristics, and survival
Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of...
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2021
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oai:doaj.org-article:324c3e5f19e348da8ee1b7ac569530b92021-12-05T12:17:48ZGermline breast cancer susceptibility genes, tumor characteristics, and survival10.1186/s13073-021-00978-91756-994Xhttps://doaj.org/article/324c3e5f19e348da8ee1b7ac569530b92021-12-01T00:00:00Zhttps://doi.org/10.1186/s13073-021-00978-9https://doaj.org/toc/1756-994XAbstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.Peh Joo HoAlexis J. KhngHui Wen LohWeang-Kee HoCheng Har YipNur Aishah Mohd-TaibVeronique Kiak Mien TanBenita Kiat-Tee TanSu-Ming TanErn Yu TanSwee Ho LimSuniza JamarisYirong SimFuh Yong WongJoanne NgeowElaine Hsuen LimMei Chee TaiEldarina Azfar WijayaSoo Chin LeeChing Wan ChanShaik Ahmad BuhariPatrick M. Y. ChanJuliana J. C. ChenJaime Chin Mui SeahWai Peng LeeChi Wei MokGeok Hoon LimEvan WooSung-Won KimJong Won LeeMin Hyuk LeeSue K. ParkAlison M. DunningDouglas F. EastonMarjanka K. SchmidtSoo-Hwang TeoJingmei LiMikael HartmanBMCarticleBreast cancerProtein-truncating variantsOverall survivalMedicineRGeneticsQH426-470ENGenome Medicine, Vol 13, Iss 1, Pp 1-14 (2021) |
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DOAJ |
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EN |
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Breast cancer Protein-truncating variants Overall survival Medicine R Genetics QH426-470 |
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Breast cancer Protein-truncating variants Overall survival Medicine R Genetics QH426-470 Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| description |
Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions. |
| format |
article |
| author |
Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman |
| author_facet |
Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman |
| author_sort |
Peh Joo Ho |
| title |
Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_short |
Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_full |
Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_fullStr |
Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_full_unstemmed |
Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_sort |
germline breast cancer susceptibility genes, tumor characteristics, and survival |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/324c3e5f19e348da8ee1b7ac569530b9 |
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