RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis

Mutations in RAD51 gene are believed to be associated with elevated breast cancer risk. However, several case–control studies focusing on the association between RAD51 135G>C and breast cancer risk failed to achieve consensus. To clarify the effect of RAD51 135G>C polymorphism on breast cancer, a meta-analysis was performed. By searching PubMed and EMBASE, a total of 14 case–control studies, containing 12,183 cases and 10,183 controls, were included. The strength of association between RAD51 135G>C polymorphism and breast cancer risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95% CI). When all the eligible studies were pooled into the meta-analysis, an elevated cancer risk was revealed in additive model (OR, 1.34; 95% CI, 1.01–1.78; P = 0.044) and recessive model (OR, 1.37; 95% CI, 1.03–1.82; P = 0.032). In subgroup analyses by ethnicity, BRCA1/2 mutation status, and family history, a significant association was found only among BRCA2 mutation carriers (additive model: OR, 4.92; 95% CI, 1.11–21.83; P = 0.036; recessive model: OR, 4.88; 95% CI, 1.10–21.67; P = 0.037). Sensitivity analysis did not perturb the results. In conclusion, this meta-analysis suggests that RAD51 variant 135C homozygote is associated with elevated breast cancer risk among BRCA2 mutation carriers.     

RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects

RAD51 plays a key role in homologous recombination repair of double-stranded DNA breaks which may cause chromosomal breaks and genomic instability. We performed a meta-analysis of 9 epidemiological studies involving 13,241 cases and 13,203 controls that examined the association between RAD51 135G>C polymorphism and breast cancer. No significant association of RAD51 135G>C polymorphism with breast cancer was found in overall and European populations. However, after the studies which did not fulfill Hardy–Weinberg equilibrium were excluded, we observed an overall significant increased breast cancer risk (for the recessive model CC vs. GG/CG: OR = 1.35, 95% CI = 1.05–1.74, P _{heterogeneity} = 0.06). In summary, our meta-analysis suggested the RAD51 135G>C polymorphism may contribute to breast cancer susceptibility.     

RAD51 G135C polymorphism is associated with breast cancer susceptibility: a meta-analysis involving 22,399 subjects

Several studies have investigated the associations between RAD51 G135C polymorphism and the susceptibility to breast cancer, but results have been inconclusive. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 17 case control studies, including 12,153 cases and 10,245 controls, were selected. Overall, significant decreased risk was found for the additive model (OR = 0.995, 95% CI = 0.991–0.998) and dominant model (OR = 0.994, 95% CI = 0.991–0.998). In the subgroup analysis by ethnicity, statistically significantly decreased risk was found in Asians (additive model: OR = 0.977, 95% CI = 0.954–1.000 and dominant model: OR = 0.981, 95% CI = 0.963–1.000). In conclusion, this meta-analysis suggests that the RAD51 G135C polymorphism is a low-penetrant risk factor for developing breast cancer.     

Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update

Among women with a mutation in BRCA1 or BRCA2, the risk of breast cancer is high, but it may be modified by exogenous and endogenous factors. There is concern that exposure to carcinogens in cigarette smoke may increase the risk of cancer in mutation carriers. We conducted a matched case–control study of 2,538 cases of breast cancer among women with a BRCA1 (n = 1,920) or a BRCA2 (n = 618) mutation. One non-affected mutation carrier control was selected for each case, matched on mutation, country of birth, and year of birth. Odds ratios were calculated using conditional logistic regression, adjusted for oral contraceptive use and parity. Ever-smoking was not associated with an increased breast cancer risk among BRCA1 carriers (OR = 1.09; 95% CI 0.95–1.24) or among BRCA2 carriers (OR = 0.81; 95% CI 0.63–1.05). The result did not differ when cases were restricted to women who completed the questionnaire within two years of diagnosis. A modest, but significant increase in risk was seen among BRCA1 carriers with a past history of smoking (OR = 1.27; 95% CI 1.06–1.50), but not among current smokers (OR = 0.95; 0.81–1.12). There appears to be no increase in the risk of breast cancer associated with current smoking in BRCA1 or BRCA2 carriers. There is a possibility of an increased risk of breast cancer among BRCA1 carriers associated with past smoking. There may be different effects of carcinogens in BRCA mutation carriers, depending upon the timing of exposure. Other members of the Hereditary Breast Cancer Clinical Study Group: Olufunmilayo Olopade, Shelly Cummings, Fergus Couch, Barry Rosen, Dominique Stoppa-Lyonnet, Ruth Gershoni-Baruch, David Horsman, Teresa Wagner, Howard Saal, Ellen Warner, Wendy Meschino, Kenneth Offit, Amber Trivedi, Michael Osborne, Dawna Gilchrist, Charis Eng, Jeffrey Weitzel, Wendy McKinnon, Marie Wood, Christine Maugard, Barbari Pasini, Peter Ainsworth, Kevin Sweet, Boris Pasche, Beth Karlan, Raluca N. Kurz, Anna Tulman, Ed Lemire, Jane Mclennan, Gareth Evans, Tomas Byrski, Tomas Huzarski, Jacek Gronwald, Bohdan Gorski, Eitan Friedman, Andrea Eisen, Mary Daly, Judy Garber, Sofia Merajver.     

A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.     

Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects

The association between a single-nucleotide polymorphism (SNP) −174G > C (rs1800795) located in the IL-6 gene promoter and breast cancer risk is still controversial and ambiguous. We performed in this study a more precise estimation of the relationship by meta-analyzing the currently available evidence from literature. A total of 11 publications containing 12 studies including 10,137 cases and 15,566 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. When all the studies were pooled into the meta-analysis, there was no evidence showing a significant association between −174G > C and breast cancer risk (for CC vs. GG: OR = 1.024, 95% CI: 0.935–1.121; for GC vs. GG: OR = 1.008, 95% CI: 0.946-1.073; for dominant model: OR = 0.980, 95% CI: 0.857–1.121; and for recessive model: OR = 1.027, 95% CI: 0.944–1.117). In the subgroup analyses by ethnicity, no significant associations were observed in any genetic models. In summary, the present meta-analysis suggests that the functional polymorphism −174G > C within the IL-6 gene promoter is not associated with breast cancer risk. Identifying a unique SNP as a breast cancer risk predictor remains a very challenging task.     

Breast cancer risk reduction associated with the RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland.

The observed heterogeneity of breast cancer risk among women who carry the same BRCA1 mutation suggests the existence of modifying environmental and genetic factors. The product of the RAD51 gene functions with BRCA1 and BRCA2 in the repair of double-stranded DNA breaks. To establish whether polymorphic variation of RAD51 modifies risk for hereditary breast cancer, we conducted a matched case-control study on 83 pairs of female carriers of the BRCA1 5382insC mutation. Cases consisted of women with breast cancer, and controls were women with the same mutation but who were unaffected. The frequency of the RAD51 135C variant allele was established in cases and controls using RFLP-PCR. The RAD51 135C allele was detected in 37% of unaffected and in 17% of affected BRCA1 carriers. Among 27 discordant matched pairs, the RAD51 135C allele was found in the healthy carrier on 22 occasions and in the affected carrier on only five occasions (odds ratio = 0.23; 95% confidence interval, 0.07-0.62; P = 0.0015). This finding suggests that RAD51 is a genetic modifier of breast cancer risk in BRCA1 carriers in the Polish population. It will be of interest to confirm this in other populations as well.     

MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish–Ashkenazi descent

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi–Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41–10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69–2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.     

Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a meta-analysis

Previous epidemiological studies have evaluated the association between the ABCB1 polymorphism and the risk of breast cancer with conflicting results. Hence, we conducted a meta-analysis of the ABCB1 gene and risk of breast cancer to obtain the most reliable estimate of the association. PubMed, Embase, and Web of Science databases were searched. A total of eight studies including 3,829 cases and 6,193 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of associations between the ABCB1 C3435T and rs2214102 G>A polymorphisms and risk of breast cancer. Of these studies, only one deviated from Hardy–Weinberg equilibrium. Summary estimates indicated that the ABCB1 C3435T polymorphism was not associated with increased risk of breast cancer in the allele contrast model (T vs. C, pooled OR = 1.15; 95% CI = 0.89–1.48); the co-dominant model (CT vs. CC, OR = 1.12 [0.86–1.46] and TT vs. CC, OR = 1.30 [0.79–2.15]); the dominant model (OR = 0.80 [0.63–1.02]; and the recessive model (OR = 0.83 [0.57–1.22]). In the sensitivity analysis by ethnicity, no statistically significant associations were detected in Asians. However, in Caucasian women the T allele contrast model and the TT genotype were each associated with increased risk: T vs. C, pooled OR (95% CI) = 1.26 (1.04–1.52) and TT vs. CC, OR = 1.48 (1.04–2.11). Accordingly, the dominant model yielded statistically significant results (pooled OR = 0.71, 95% CI: 0.52–0.96) but not with the allele contrast model or the co-dominant model. There was evidence of publication bias (P = 0.02 for recessive model). In conclusion, there is limited evidence to indicate that the ABCB1 C3435T and rs2214102 G>A polymorphisms are associated with increased risk of breast cancer.     

NBS1 8360G?>?C polymorphism is associated with breast cancer risk: a meta-analysis

NBS1 gene plays an important role in DNA repair. Many epidemiological studies have investigated the association between NBS1 8360G > C polymorphism and breast cancer, however, the results are still controversial. Therefore, we performed a meta-analysis of 10 case–control studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results showed NBS1 8360G > C polymorphism contributed to breast risk in overall populations (for CC vs. GG: OR = 0.75, 95% CI = 0.74–0.98, P = 0.13 for heterogeneity; for the recessive model CC vs. GG/CG: OR = 0.88, 95% CI = 0.77–1.00, P = 0.44 for heterogeneity). In subgroup analysis by ethnicity, no significant association was found in all genetic models. In summary, our meta-analysis strongly suggests the NBS1 8360G > C polymorphism is associated with breast cancer.     

No association between a progesterone receptor gene promoter polymorphism (+331G>A) and breast cancer risk in Caucasian women: evidence from a literature-based meta-analysis

Sex steroid hormones and their receptors such as estrogen receptor (ER) and progesterone receptor (PgR) have been widely studied for their roles in the etiology of breast cancer. To date, many studies have evaluated the association between a functional polymorphism in the PgR gene promoter (+331G>A, rs10895068) and breast cancer risk; however, the result is still ambiguous and inconclusive. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. By searching relevant literature, a total of 10 studies containing 13,702 cases and 14,726 controls (28,428 subjects in total) were identified and meta-analyzed. All the study subjects were Caucasian women. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, dominant model, and recessive model. Overall, no significant association between +331G>A polymorphism and breast cancer susceptibility was observed for AA versus GG (OR = 0.940, 95% CI: 0.566–1.562), GA versus GG (OR = 1.061, 95% CI: 0.888–1.267), AA + GA versus GG (OR = 1.074, 95% CI: 0.956–1.207), and AA versus GA + GG (OR = 0.951, 95% CI: 0.586–1.544). Sensitivity analysis was performed by limiting the meta-analysis to those studies fulfilling Hardy–Weinberg equilibrium, and the results were not materially altered in any genetic model. In conclusion, the present meta-analysis strongly suggests that +331G>A in the PgR gene is not associated with breast cancer risk.     

Synergistic interaction of variants in CHEK2 and BRCA2 on breast cancer risk

We studied the effects of BRCA2 and CHEK2 variants on breast cancer risk in two case-control series from Poland and Belarus. The missense BRCA2 variant T1915M was associated with a significant reduction in breast cancer risk (OR = 0.62; 95% CI 0.49–0.79; P = 0.0007). Modest increases of breast cancer risk were observed for the four analysed CHEK2 variants (I157T, 1100delC, IVS2 + 1G > A and del5395) (OR = 2.2; 95% 1.7–2.8; P = 0.0001). The highest risk was observed among women who carried both a BRCA2 and a CHEK2 variant (OR = 5.7; 95% CI 1.7–19; P = 0.006). We observed a statistically significant interaction effect between CHEK2 mutations and the BRCA2 substitution (P = 0.03). These data suggest that the BRCA2 T1915M polymorphism alone might be associated with a reduced risk of breast cancer, but among CHEK2 mutation carriers, it may lead to an unexpectedly high risk.

BRCA2 N372H polymorphism and breast cancer susceptibility: a meta-analysis involving 44,903 subjects

Published data on the association between BRCA2 N372H polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 22 studies including 22,515 cases and 22,388 controls were involved in this meta-analysis. Overall, no significant associations were found between BRCA2 N372H polymorphism and breast cancer risk when all studies pooled into the meta-analysis (NH versus NN: OR = 1.01, 95% CI = 0.97–1.05; HH versus NN: OR = 1.05, 95% CI = 0.97–1.13; dominant model: OR = 1.01, 95% CI = 0.98–1.05; and recessive model: OR = 1.05, 95% CI = 0.98–1.13). In the subgroup analysis by ethnicity, still no significant associations were found for Caucasians, Asians, or Africans. When stratified by study design, statistically significantly elevated risk was found for 372H allele based on population-based studies (HH versus NN: OR = 1.11, 95% CI = 1.01–1.21; dominant model: OR = 1.05, 95% CI = 1.00–1.10; recessive model: OR = 1.09, 95% CI = 1.00–1.18). In conclusion, this meta-analysis suggests that the BRCA2 372H allele may be a low-penetrant risk factor for developing breast cancer. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

The association between two polymorphisms of eNOS and breast cancer risk: a meta-analysis

Breast cancer is one of the most common malignant tumors worldwide. Endothelial nitric oxide synthase (eNOS) plays a key role in breast cancer development. The associations between the two eNOS polymorphisms (E298D rs1799983, −786T>C rs2070744) and breast cancer risk are inconclusive. A meta-analysis was performed in this study. By searching Medline, ISI Web of Knowledge, ScienceDirect, EBSCO, CNKI, and SinoMed database, six case–control studies were collected for the eNOS E298D polymorphism (3,038 cases and 2,508 controls) and three case–control studies were eligible for the eNOS −786T>C polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the two eNOS polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, significantly decreased risk was observed for E298D (for EE vs. DD: OR = 0.74, 95% CI = 0.59–0.94; for ED vs. DD: OR = 0.78, 95% CI = 0.61–0.98; for dominant model: OR = 0.77, 95% CI = 0.61–0.96) and −786T > C (for TT vs. CC: OR = 0.60, 95% CI = 0.42–0.86; for dominant model: OR = 0.66, 95% CI = 0.47–0.94). In the subgroup analysis by ethnicity, significant decreased risks were found for E298D (for EE vs. DD: OR = 0.75, 95% CI = 0.56–0.99) and −786T>C (for TT vs. CC: OR = 0.53, 95% CI = 0.35–0.81; for dominant model: OR = 0.61, 95% CI = 0.41–0.91; for recessive model: OR = 0.70, 95% CI = 0.55–0.91) among Caucasians; significant decreased risks were observed for E298D (for ED vs. DD: OR = 0.12, 95% CI = 0.02–0.96; for dominant model: OR = 0.13, 95% CI = 0.02–1.00) among Asians. In conclusion, this meta-analysis suggests that both eNOS E298D and −786T>C polymorphisms are associated with reduced breast cancer risk.     

P53 codon 72 polymorphism contributes to breast cancer risk: a meta-analysis based on 39 case–control studies

P53 is a tumor suppressor gene and plays important roles in the etiology of breast cancer. Studies revealing conflicting results on the role of p53 codon 72 polymorphism (G>C) on breast cancer risk led us to perform a meta-analysis to investigate this relationship. Thirty-nine published studies, including 26,041 breast cancer cases and 29,679 controls were identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results suggested that the variant genotypes were associated with a significantly reduced breast cancer risk (GC vs. GG: OR = 0.91, 95% CI: 0.83–1.00; CC/GC vs. GG: OR = 0.90, 95% CI: 0.82–0.99). In the stratified analyses, significantly decreased risks were also found among European populations (GC vs. GG: OR = 0.89, 95% CI: 0.80–0.99; CC/GC vs. GG: OR = 0.88, 95% CI: 0.80–0.98) and studies with population-based controls (GC vs. GG: OR = 0.88, 95% CI: 0.78–0.98; CC/GC vs. GG: OR = 0.87, 95% CI: 0.78–0.97). The results suggested that p53 codon 72 polymorphism may contribute to susceptibility to breast cancer, especially in Europeans. Additional well-designed large studies were required to validate this association in different populations.     

Association between CYP19 polymorphisms and breast cancer risk: results from 10,592 cases and 11,720 controls

The association of CYP19 gene polymorphisms with breast cancer has been widely reported, but results of previous studies were somewhat contradictory and underpowered. In order to overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis including three CYP19 gene polymorphisms [R264C polymorphism, CYP19_630 3-bp del/Ins polymorphism, and CYP19_681 (TTTA)_n polymorphisms]. A total of 22 studies with 10,592 cases and 11,720 controls were identified, and the results showed that R264C polymorphism was not associated with breast cancer risk in overall (T vs. C: OR = 1.061, 95% CI = 0.929–1.212) or race-based populations (T vs. C for Asian: OR = 1.169, 95% CI = 1.002–1.363; for Caucasian: OR = 0.787, 95% CI = 0.597–1.037); meanwhile, for Asian individuals, 3-bpDel/Ins polymorphism showed a significantly association with breast cancer susceptibility (for allele Del vs. allele Ins: OR = 1.278, 95% CI = 1.066–1.532) while the carriers of allele (TTTA)₁₂ can significantly decrease breast cancer risk (OR = 0.752, 95% CI = 0.603–0.939). Furthermore, the carriers of allele (TTTA)₁₀ were significantly associated with breast cancer susceptibility (OR = 1.515, 95% CI = 1.115–2.058). It can be concluded that potentially functional CYP19_630 3-bp del/Ins polymorphism and CYP19_681 (TTTA)_n polymorphisms may play a low penetrance role in breast cancer susceptibility in an ethnicity-specific manner.     

A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The RAD51 gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the BRCA1 and BRCA2 gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP), RAD51-135g-->c, in the 5' untranslated region of the gene has been found to elevate breast cancer (BC) risk among BRCA2 carriers. We genotyped 309 BRCA1/2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the RAD51-135g-->c SNP. Risk analyses were conducted using COX proportional hazard models for the BRCA1/2 carriers and simple logistic regression analysis for the noncarrier case-control population. BRCA2 carriers were also studied using logistic regression and Kaplan-Meier survival analyses. The estimated BC hazard ratio (HR) for RAD51-135c carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85-1.90, P=0.23) for BRCA1/2 carriers, and 2.09 (95% CI 1.04-4.18, P=0.04) when the analysis was restricted to BRCA2 carriers. The median BC age was younger in BCRA2-RAD51-135c carriers (45 (95% CI 36-54) vs 52 years (95% CI 48-56), P=0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5-58.8, P=0.163). In noncarrier BC cases, carrying RAD51-135c was not associated with BC risk (0.97; 95% CI 0.47-2.00). These results indicate significantly elevated risk for BC in carriers of BRCA2 mutations who also carry a RAD51-135c allele. In BRCA1 carriers and noncarriers, no effect for this SNP was found.     

Germline RAP80 mutations and susceptibility to breast cancer

Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5′UTR (c.-8A > G) and a variant in the 3′UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2–5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.     

Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: effects of oral contraceptive use and parental origin of mutation

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n = 638) or BRCA2 (n = 250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65 ± 12.2 years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8 ± 10.8 years) and the rest (n = 373−42%) were asymptomatic carriers (age at counseling 40.7 ± 10.6 years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5 years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR = 1.84 95% CI 1.465–2.314, P = 0.001) and paternal compared with maternal origin of mutation (OR = 1.55 95% CI 1.14–2.12, P = 0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.     

MTHFR C677T polymorphism associated with breast cancer susceptibility: a meta-analysis involving 15,260 cases and 20,411 controls

Published data on the association between MTHFR C677T polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR C677T polymorphism and breast cancer risk. The pooled ORs were performed with co-dominant model (CT vs. CC, TT vs. CC), dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT), respectively. A total of 37 studies including 15,260 cases and 20,411 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with TT variant genotype in homozygote comparison and dominant genetic model when all studies were pooled into the meta-analysis (TT vs. CC: OR = 1.11, 95% CI = 1.01–1.23; dominant model: OR = 1.04, 95% CI = 1.00–1.09). In the subgroup analysis by ethnicity, significantly increased risks were found for TT allele carriers among Asians (TT vs. CC: OR = 1.18, 95% CI = 1.04–1.35; recessive model: OR = 1.15, 95% CI = 1.03–1.29). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TT vs. CC: OR = 1.18, 95% CI = 1.02–1.38; recessive model: OR = 1.17, 95% CI = 1.05–1.29). In the subgroup analysis by menopausal status, statistically significantly increased risk was found among postmenopausal women (CT vs. CC: OR = 1.12, 95% CI = 1.02–1.23; dominant model: OR = 1.11, 95% CI = 1.01–1.22). In conclusion, this meta-analysis suggests that the MTHFR T allele is a low-penetrant risk factor for developing breast cancer.