Germline breast cancer susceptibility genes, tumor characteristics, and survival
Creators: name: Ho, Peh Joo
name: Khng, Alexis J.
name: Loh, Hui Wen
name: Ho, Weang-Kee
name: Yip, Cheng Har
name: Mohd-Taib, Nur Aishah
name: Tan, Veronique Kiak Mien
name: Tan, Benita Kiat-Tee
name: Tan, Su-Ming
name: Tan, Ern Yu
name: Lim, Swee Ho
name: Jamaris, Suniza
name: Sim, Yirong
name: Wong, Fuh Yong
name: Ngeow, Joanne
name: Lim, Elaine Hsuen
name: Tai, Mei Chee
name: Wijaya, Eldarina Azfar
name: Lee, Soo Chin
name: Chan, Ching Wan
name: Buhari, Shaik Ahmad
name: Chan, Patrick M. Y.
name: Chen, Juliana J. C.
name: Seah, Jaime Chin Mui
name: Lee, Wai Peng
name: Mok, Chi Wei
name: Lim, Geok Hoon
name: Woo, Evan
name: Kim, Sung-Won
name: Lee, Jong Won
name: Lee, Min Hyuk
name: Park, Sue K.
name: Dunning, Alison M.
name: Easton, Douglas F.
name: Schmidt, Marjanka K.
name: Teo, Soo-Hwang
name: Li, Jingmei
name: Hartman, Mikael
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Research
Breast cancer
Protein-truncating variants
Overall survival

description: 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 &lt; 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.