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). p. 185. 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. © 2021, The Author(s).

Item Type: Article
Funders: European Union’s Horizon 2020 Research and Innovation Programme (BRIDGES: grant number 634935), Wellcome Trust [grant no: v203477/Z/16/Z], National Research Foundation Singapore [NRF-NRFF2017-02, awarded to J Li], NUS start-up Grant [awarded to MH], National University Cancer Institute Singapore (NCIS) Centre Grant [NMRC/CG/NCIS/2010, NMRC/CG/012/2013 and CGAug16M005, awarded to MH], Breast Cancer Prevention Programme (BCPP, awarded to MH), Asian Breast Cancer Research Fund [awarded to MH], NMRC Clinician Scientist Award (SI Category) [NMRC/CSA-SI/0015/2017, awarded to MH], NMRC Centre Grant [CGAug16M012, awarded to EYT], MyBrCa is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06), Cancer Research Malaysia
Uncontrolled Keywords: Breast cancer; Overall survival; Protein-truncating variants
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 29 Dec 2021 04:04
Last Modified: 29 Dec 2021 04:04

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