Germline breast cancer susceptibility genes, tumor characteristics, and survival

Germline breast cancer susceptibility genes, tumor characteristics, and survival

Genome Medicine

10.1186/s13073-021-00978-9

http://dx.doi.org/10.1186/s13073-021-00978-9

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

Molecular Biology, Molecular Medicine, Genetics(clinical), genetics

02 December 2021

Ho, P. J., Khng, A. J., Loh, H. W., Ho, W.-K., Yip, C. H., Mohd-Taib, N. A., Tan, V. K. M., Tan, B. K.-T., Tan, S.-M., Tan, E. Y., Lim, S. H., Jamaris, S., Sim, Y., Wong, F. Y., Ngeow, J., Lim, E. H., Tai, M. C., Wijaya, E. A., Lee, S. C., … Hartman, M. (2021). Germline breast cancer susceptibility genes, tumor characteristics, and survival. Genome Medicine, 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation Singapore - NRF Fellowship
Grant Reference no. : NRF-NRFF2017-02

This research / project is supported by the National University Cancer Institute Singapore (NCIS) - Centre Grant
Grant Reference no. : NMRC/CG/NCIS/2010, NMRC/CG/012/2013 and CGAug16M005

This research / project is supported by the National Medical Research Council (NMRC) - Clinician Scientist Award (SI Category)
Grant Reference no. : NMRC/CSA- SI/0015/2017

This research / project is supported by the National Medical Research Council (NMRC) - Centre Grant
Grant Reference no. : CGAug16M012

This research / project is supported by the National University Singapore (NUS) - Start-up Grant
Grant Reference no. : NA

This research / project is supported by the Saw Swee Hock School of Public Health - Breast Cancer Prevention Programme (BCPP)
Grant Reference no. : NA

This research / project is supported by the National University Singapore (NUS) - Breast Cancer Research Fund
Grant Reference no. : NA

Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06), the Wellcome Trust [grant no: v203477/Z/16/Z], and Cancer Research Malaysia

https://oar.a-star.edu.sg/communities-collections/articles/18167

1756-994X

Genome Institute of Singapore

http://dx.doi.org/10.1186/s13073-021-00978-9