Germline breast cancer susceptibility genes, tumor characteristics, and survival
Document Type
Article
Publication Date
1-1-2021
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).
Keywords
Breast cancer, Overall survival, Protein-truncating variants
Divisions
fac_med
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
Publication Title
Genome Medicine
Volume
13
Issue
1
Publisher
BMC