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Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk.

ABSTRACT: Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the 3'UTR of BRCA1 and haplotypes containing these functional polymorphisms may be associated with breast cancer risk. We sequenced the BRCA1 3'UTR from breast cancer patients to identify miRNA disrupting polymorphisms. We further evaluated haplotypes of this region including the identified 3'UTR variants in a large population of controls and breast cancer patients (n = 221) with known breast cancer subtypes and ethnicities. We identified three 3'UTR variants in BRCA1 that are polymorphic in breast cancer populations, and haplotype analysis including these variants revealed that breast cancer patients harbor five rare haplotypes not generally found among controls (9.50% for breast cancer chromosomes, 0.11% for control chromosomes, p = 0.0001). Three of these rare haplotypes contain the rs8176318 BRCA1 3'UTR functional variant. These haplotypes are not biomarkers for BRCA1 coding mutations, as they are found rarely in BRCA1 mutant breast cancer patients (1/129 patients = 0.78%). These rare BRCA1 haplotypes and 3'UTR SNPs may represent new genetic markers of breast cancer risk.

SUBMITTER: Pelletier C

PROVIDER: S-EPMC3048078 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk.

Pelletier Cory C Speed William C WC Paranjape Trupti T Keane Katie K Blitzblau Rachel R Hollestelle Antoinette A Safavi Kyan K van den Ouweland Ans A Zelterman Daniel D Slack Frank J FJ Kidd Kenneth K KK Weidhaas Joanne B JB

Cell cycle (Georgetown, Tex.) 20110101 1

Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the ...[more]

PMID: 21191178

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Project description:Numerous common genetic variants have been linked to breast cancer risk, but they only partially explain the total breast cancer heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of breast cancer risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for breast cancer. With computationally phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-breast cancer association analysis was conducted using sliding windows of 5 to 500 consecutive array-genotyped variants. In the discovery stage, haplotype-breast cancer associations were evaluated retrospectively in the prestudy-enrollment data including 5,487 breast cancer cases. Breast cancer hazard ratios (HR) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of breast cancer at enrollment, of whom 3,524 later developed breast cancer. This two-stage analysis detected 13 rare loci (frequency <1%), each associated with an appreciable breast cancer-risk increase (discovery: HRs = 2.84-6.10, P < 5 × 10-8; replication: HRs = 2.08-5.61, P < 0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in breast cancer-related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case-control study, 6 of the 13 rare-loci associations were found generalizable (odds ratio estimates: 1.48-7.67, P < 0.05). This study demonstrates the complementary advantage of utilizing rare haplotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large data sets of germline whole-genome sequencing become available.SignificanceA genome-wide two-stage haplotype analysis identifies rare haplotypes associated with breast cancer risk and suggests that the rare risk haplotypes represent long-range interactions with regulatory consequences influencing cancer risk.

Project description:BackgroundGenome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk.MethodsThe coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied.ResultsLoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants).ConclusionsOur data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.

Project description:A 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.The 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.Luciferase 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.A 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.

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Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk.

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Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk.

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