A germline mutation in the BRCA13’UTR predicts Stage IV breast cancer

Abstract

BackgroundA germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer.MethodsThe impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont.ResultsLuciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort.ConclusionA variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.

SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk

“…MiRNA hsa-miR-525-5p also was downregulated in tumor as compared to non-tumor tissue (p = 0.0044) and rs8176318 was significantly associated with an increase in risk of colon cancer (OR AA 1.34 95% CI 1.01, 1.78). This variant has been reported as being associated with decreased BRCA1 expression, increased breast cancer risk, and greater likelihood of having stage IV breast cancer [ 56 ]. Expression levels of this miRNA are somewhat low, and may therefore less precise, however, together these findings could support the claim that the SNP rs8176318 contributes to the incidence and progression of some breast and colon cancers through altered miRNA regulation within these tissues.…”

Breast Cancer and miR-SNPs: The Importance of miR Germ-Line Genetics

“…BRCA1: A functional SNP, rs8176318, located in the 3′UTR of BRCA1, has been reported to predict breast (including TNBC) and ovarian cancer risk in a population of Irish women [30]. This SNP is also influenced by estrogen exposure, implying that the variant poses an elevated risk of developing cancer at menopause or upon estrogen withdrawal.…”

A genome-wide scan for candidate lethal variants in Thoroughbred horses

“…During this time, trophoblast cells rapidly proliferate to form the chorionic girdle, which then invades the endometrium to form epithelial cups (59). It is possible that LY49B is important for successful implantation of the embryo by mediating the action of MHC-1 which is expressed during this time (60,61). However, it is also possible that loss of function in LY49B may result in post-natal juvenile death, which would explain the lack of homozygotes seen in our data.…”