Abstract
BackgroundThe tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development.ResultsWe found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells.MethodsWe investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility.ConclusionsGenetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development.
Highlights
Breast cancer is a highly heterogeneous disease with distinct molecular and clinical phenotypes
It is suggested that genetic variant of multiple low-risk polymorphisms of genes encoding BRCA1/BRCA2 interacting proteins may be associated with risk of triple-negative breast cancer (TNBC) [5,6,7,8,9,10]
We carried out a systematic analysis of 37 genetic variants in genes from the BRCA1 associated A complex including ABRAXAS, BRCC36, RAP80 BRE and NBA1, in a Chinese Han Women cohort, including 414 triple-negative breast cancer (TNBC) cases and 354 controls
Summary
Breast cancer is a highly heterogeneous disease with distinct molecular and clinical phenotypes. A recent comprehensive analysis of The Cancer Genome Atlas (TCGA) program showed that around twenty percent of basal-like breast tumors have an inherited or somatic BRCA1 or BRCA2 nucleic acid variant [4]. The deleterious mutations in BRCA1/BRCA2 are tightly associated with development of TNBC. It is suggested that genetic variant of multiple low-risk polymorphisms of genes encoding BRCA1/BRCA2 interacting proteins may be associated with risk of TNBC [5,6,7,8,9,10]. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development
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