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Title: Germline breast cancer susceptibility genes, tumor characteristics, and survival
Authors: Ho, Peh Joo 
Khng, Alexis J.
Loh, Hui Wen
Ho, Weang-Kee
Yip, Cheng Har
Mohd-Taib, Nur Aishah
Tan, Veronique Kiak Mien
Tan, Benita Kiat-Tee 
Tan, Su-Ming
Tan, Ern Yu
Lim, Swee Ho
Jamaris, Suniza
Sim, Yirong
Wong, Fuh Yong
Ngeow, Joanne
Lim, Elaine Hsuen
Tai, Mei Chee
Wijaya, Eldarina Azfar
Lee, Soo Chin 
Chan, Ching Wan 
Buhari, Shaik Ahmad 
Chan, Patrick M. Y.
Chen, Juliana J. C.
Seah, Jaime Chin Mui
Lee, Wai Peng
Mok, Chi Wei
Lim, Geok Hoon
Woo, Evan
Kim, Sung-Won
Lee, Jong Won
Lee, Min Hyuk
Park, Sue K.
Dunning, Alison M.
Easton, Douglas F.
Schmidt, Marjanka K.
Teo, Soo-Hwang
Li, Jingmei 
Hartman, Mikael 
Keywords: Breast cancer
Overall survival
Protein-truncating variants
Issue Date: 1-Dec-2021
Publisher: BioMed Central Ltd
Citation: Ho, Peh Joo, Khng, Alexis J., Loh, Hui Wen, Ho, Weang-Kee, Yip, Cheng Har, Mohd-Taib, Nur Aishah, Tan, Veronique Kiak Mien, Tan, Benita Kiat-Tee, Tan, Su-Ming, Tan, Ern Yu, Lim, Swee Ho, Jamaris, Suniza, Sim, Yirong, Wong, Fuh Yong, Ngeow, Joanne, Lim, Elaine Hsuen, Tai, Mei Chee, Wijaya, Eldarina Azfar, Lee, Soo Chin, Chan, Ching Wan, Buhari, Shaik Ahmad, Chan, Patrick M. Y., Chen, Juliana J. C., Seah, Jaime Chin Mui, Lee, Wai Peng, Mok, Chi Wei, Lim, Geok Hoon, Woo, Evan, Kim, Sung-Won, Lee, Jong Won, Lee, Min Hyuk, Park, Sue K., Dunning, Alison M., Easton, Douglas F., Schmidt, Marjanka K., Teo, Soo-Hwang, Li, Jingmei, Hartman, Mikael (2021-12-01). Germline breast cancer susceptibility genes, tumor characteristics, and survival. Genome Medicine 13 (1) : 185. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2021, The Author(s).
Source Title: Genome Medicine
ISSN: 1756-994X
DOI: 10.1186/s13073-021-00978-9
Rights: Attribution 4.0 International
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