Germline breast cancer susceptibility genes, tumor characteristics, and survival.
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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 MY
Chen, Juliana JC
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
Hartman, Mikael
Publication Date
2021-12-02Journal Title
Genome Med
ISSN
1756-994X
Publisher
Springer Science and Business Media LLC
Volume
13
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ho, P. J., Khng, A. J., Loh, H. W., Ho, W., Yip, C. H., Mohd-Taib, N. A., Tan, V. K. M., et al. (2021). Germline breast cancer susceptibility genes, tumor characteristics, and survival.. Genome Med, 13 (1) https://doi.org/10.1186/s13073-021-00978-9
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.
Keywords
Breast cancer, Overall Survival, Protein-truncating Variants
Sponsorship
Wellcome Trust (203477/Z/16/Z)
Identifiers
PMC8638193, 34857041
External DOI: https://doi.org/10.1186/s13073-021-00978-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332508
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