Germline breast cancer susceptibility genes, tumor characteristics, and survival
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Published:2021-12
Issue:1
Volume:13
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
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 JingmeiORCID, Hartman Mikael
Abstract
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.
Funder
National Medical Research Council National Research Foundation Singapore
Publisher
Springer Science and Business Media LLC
Subject
Genetics(clinical),Genetics,Molecular Biology,Molecular Medicine
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