The RAD51D E233G variant and breast cancer risk: population-based and clinic-based family studies of Australian women.
ABSTRACT RAD51D is a homolog of the RAD51 protein, which is known to be an important component of the DNA repair pathway. A rare missense variant in the RAD51D gene, E233G (c.A>G), has been reported to be more prevalent in breast cancer cases from specific multiple-case breast cancer families, with an odds ratio of 2.6 (95% confidence interval (CI): 1.12-6.03). We assessed whether this variant was associated with breast cancer risk using two studies: a population-based case-control-family study based on 1,110 cases and 629 controls, and a clinic-based study based on 390 cases from multiple-case breast cancer families. We conducted case-control analyses and modified segregation analyses of carrier families. The carrier frequencies (95% CI) of the RAD51D variant were 4.1% (2.4-6.6) for clinic-based cases, 3.9% (2.8-5.2) for population-based cases, and 3.7% (2.3-5.4) for population-based controls, and were not significantly higher in case groups than controls (P=0.7 and P=0.8, respectively). After genotyping the relatives of cases who carried the variant, modified segregation analyses of these families were conducted, and the estimated hazard ratio for breast cancer corresponding to the E233G variant was 1.30 (95% CI: 0.66-2.58; P=0.4) for familial breast cancer families and 1.28 (95% CI: 0.47-3.43; P=0.6) for families unselected for family history. Therefore, despite being well powered to detect moderate risks, no evidence for an association between the E233G variant and breast cancer risk was observed in any setting. Larger studies would be required to determine if this variant is associated with a smaller risk of breast cancer.
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ABSTRACT: Background: To date, common genetic variants in ~70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk. Methods: We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤ 5% located in flanking 500 kb of each of the index SNPs in 67 GWAS loci. The study included 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations. Results: Single marker analyses identified 38 missense variants being association with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P=0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an odds ratio (OR) of 6.2 (95% CI:1.4-27.6, P=6.2×10-3). SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI:2.2-124.5, P=2.2×10-4). Gene-based analyses suggested eight genes associated with breast cancer risk at P<0.05, including the EFEMP2 gene (P=0.002) and the FBXO18 gene (P=0.008). Conclusion: Our results identified association of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biological mechanisms underlying the associations. Impact: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk.Cancer Epidemiology Biomarkers & Prevention 01/2014; · 4.56 Impact Factor
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ABSTRACT: RAD51D mutations have been recently identified in breast (BC) and ovarian (OC) cancer families. Although an aetiological role in OC seems to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish breast/ovarian cancer families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families, and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with HRM, DHPLC or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.667+2_667+23del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.667+2_667+23del co-segregated in the family with one early onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family © 2013 Wiley Periodicals, Inc.International Journal of Cancer 10/2013; · 6.20 Impact Factor
Article: School of Population Health MSPH