Germline breast cancer susceptibility genes, tumor characteristics, and survival

Ho, Peh Joo and Khng, Alexis J. and Loh, Hui Wen and Ho, Weang-Kee and Yip, Cheng Har and Mohd-Taib, Nur Aishah and Tan, Veronique Kiak Mien and Tan, Benita Kiat-Tee and Tan, Su-Ming and Tan, Ern Yu and Lim, Swee Ho and Jamaris, Suniza and Sim, Yirong and Wong, Fuh Yong and Ngeow, Joanne and Lim, Elaine Hsuen and Tai, Mei Chee and Wijaya, Eldarina Azfar and Lee, Soo Chin and Chan, Ching Wan and Buhari, Shaik Ahmad and Chan, Patrick M. Y. and Chen, Juliana J. C. and Seah, Jaime Chin Mui and Lee, Wai Peng and Mok, Chi Wei and Lim, Geok Hoon and Woo, Evan and Kim, Sung-Won and Lee, Jong Won and Lee, Min Hyuk and Park, Sue K. and Dunning, Alison M. and Easton, Douglas F. and Schmidt, Marjanka K. and Teo, Soo-Hwang and Li, Jingmei and Hartman, Mikael (2021) Germline breast cancer susceptibility genes, tumor characteristics, and survival. Genome Medicine, 13 (1). ISSN 1756-994X, DOI

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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.

Item Type: Article
Funders: European Union's Horizon 2020 Research and Innovation Programme (BRIDGES) [634935], Wellcome Trust European Commission [v203477/Z/16/Z], National Research Foundation, Singapore [NRF-NRFF2017-02], National University Cancer Institute Singapore (NCIS) Centre Grant [NMRC/CG/NCIS/2010]
Uncontrolled Keywords: Breast cancer; Protein-truncating variants; Overall survival
Subjects: R Medicine > R Medicine (General)
R Medicine > RD Surgery
Divisions: Faculty of Medicine
Depositing User: Ms Zaharah Ramly
Date Deposited: 17 Jul 2022 03:43
Last Modified: 17 Jul 2022 03:43

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