Abstract
“BRCAX” refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations. In this study, we report the findings of the genetic architecture of BRCAX with novel and redefined candidate loci and their potential impacts on preventive strategy. We performed a genome-wide association study involving 1,469 BRCAX cases from the Korean Hereditary Breast Cancer study, and high-risk breast cancer cases (1,482 Asians and 9,902 Europeans) from the Breast Cancer Association Consortium. We also evaluated the previously reported susceptibility loci for their roles in the high-risk breast cancers. We have identified three novel loci (PDE7B, UBL3, and a new independent marker in CDKN2B-AS1) associated with BRCAX, and replicated previously reported SNPs (24 of 92) and moderate/high-penetrance (seven of 23) genes for Korean BRCAX. For the novel candidate loci, evidence supported their roles in regulatory function. We estimated that the common low-penetrance loci might explain a substantial part of high-risk breast cancer (39.4% for Koreans and 24.0% for Europeans). Our study findings suggest that common genetic markers with lower penetrance constitute a part of susceptibility to high-risk breast cancers, with potential implications for a more comprehensive genetic screening test.
Highlights
“BRCAX” refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations
A total of 1,478 Korean BRCAX cases and 5,979 controls were selected with 3,378,933 markers
For BRCA2 gene, we found 42 variants significantly which are more frequent in the cases compared to the controls (Supplementary Table S2)
Summary
“BRCAX” refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations. The effectiveness of this screening program, is controversial mainly because the validity of mammography-based test is lower for Asian women than for Caucasians[4,5,6,7,8] About 4.8% and 11.1% of breast cancers were diagnosed before age 40 and 45, respectively, in the United States between 2005 and 2014 The proportions of these early-onset cases almost tripled for Korean women during the same period (13.9% and 29.8%), overall incidence rate is less than a half of that for MAX Institute, Seoul National University, Seoul, Republic of Korea. In Korea, breast cancer cases with early-onset (age < 40) or other indications suggesting a strong genetic burden are entitled to BRCA1/2 mutation testing covered by Korean National Health Insurance.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
