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.     

MAP3K1及LSP1基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险相关性

目的:探讨MAP3K1及LSP1基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险的关系。方法:采用多重单碱基延伸单核苷酸多态性分型技术(Snapshot)分析方法,检测280例绝经前乳腺癌患者和287例绝经前正常对照者MAP3K1基因rs889312和LSP1基因rs3817198多态性位点基因型,并比较不同基因型与乳腺癌风险的关系。结果:MAP3K1基因rs889312和LSP1基因rs3817198多态性位点基因型频率在乳腺癌和对照样本之间未存在显著差异(P=0.937、P=0.323)。Logistic回归分析结果显示,对于MAP3K1的rs889312位点,与AA携带者相比,AC携带者、CC携带者和AC+CC基因型携带者与乳腺癌的患病危险无关(OR=0.814,95%CI=0.537-1.236,P=0.335;OR=0.999,95%CI=0.627-1.594,P=0.998;OR=0.876,95%CI=0.591-1.298,P=0.509);对于LSP1的rs3817198位点,与TT携带者相比,CT携带者、CC携带者和CT+CC基因型携带者与乳腺癌的患病危险无关(OR=0.832,95%CI=0.565-1.223,P=0.349;OR=0.651,95%CI=0.108-3.936,P=0.640;OR=0.839,95%CI=0.573-1.229,P=0.369)。结论:上述两个基因MAP3K1和LSP1位点多态性与中国北方汉族绝经前妇女乳腺癌易感性之间无明显相关性。     

Glutathione S-transferase P1 Ile105Val polymorphism and breast cancer risk: a meta-analysis involving 34,658 subjects

Glutathione S-transferase P1 (GSTP1) is involved in a wide range of detoxifying reactions. Any alteration in the structure, function, or expression of GSTP1 gene may alter the ability of a cell to inactivate carcinogens or mutagens, and thus modify an individual’s risk to cancer. Previous epidemiological studies on the potential association between GSTP1 Ile105Val polymorphism and breast cancer risk have produced inconsistent results. In order to drive a more precise estimation of this association, we performed a meta-analysis of 30 published case–control studies including 15,901 cases and 18,757 controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results of this meta-analysis showed that GSTP1 Ile105Val polymorphism was not associated with breast cancer susceptibility in overall population. However, in subgroup analysis by ethnicity, we found a significant association among Asian population (for Val/Val vs. Ile/Ile: OR 1.27, 95% CI 1.02–1.83; for the recessive model Val/Val vs. Ile/Ile + Ile/Val: OR 1.42, 95% CI 1.20–1.69). When stratified by study design, significantly elevated susceptibility to breast cancer was found among hospital-based studies (for Val/Val vs. Ile/Ile: OR 1.38, 95% CI 1.16–1.63; for recessive model Val/Val vs. Ile/Val + Ile/Ile: OR 1.31, 95% CI 1.12–1.55; for dominant model: Val/Val + Ile/Val vs. Ile/Ile: OR 1.10, 95% CI 1.02–1.19). In conclusion, our meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase susceptibility to breast cancer in Asian population.     

Novel breast cancer risk alleles and endometrial cancer risk

Genome-wide association studies have identified several novel risk alleles for breast cancer. We hypothesized that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between these 7 newly identified risk alleles for breast cancer and endometrial cancer risk using 692 invasive endometrial cancer cases and 1,723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In contrast to the breast cancer findings, we did not observe an increased risk of endometrial cancer. We observed an inverse association among rs2981582 (FGFR2) variant carriers [OR= 0.75 (95% CI: 0.60-0.95)]. We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk. We did not observe associations with the other single nucleotide polymorphisms (SNPs) and endometrial cancer risk. Replication studies investigating these polymorphisms and endometrial cancer risk are warranted. However, our findings do suggest the potential importance of biological differences between endometrial and breast cancer with respect to the genes identified in the scans. The molecular mechanisms underlying these differences remain to be defined.     

Potentially functional polymorphisms in <Emphasis Type="Italic">ESR1</Emphasis> and breast cancer risk: a meta-analysis

Estrogen exposure is a central risk factor in the development of breast cancer. Estrogen receptor alpha (coded by ESR1) is the key mediator of estrogen response in mammary tissue. Genetic changes altering the expression of ESR1 is likely to affect breast cancer susceptibility. Since the identification of several potentially functional polymorphisms in ESR1 (rs2234693, rs9340799, rs1801132, rs3798577, rs2228480), molecular epidemiological studies were conducted in recent years to evaluate the association between polymorphisms and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This current analysis on 10,300 breast cancer cases and 16,620 controls on rs2234693 showed a borderline significant decreased breast cancer risk for CC and CC/CT carriers (CC vs. TT: OR, 0.92, 95% CI, 0.86–0.99; CC/CT vs. TT: OR, 0.95, 95% CI, 0.89–1.00). Variant genotypes of the rs1801132 polymorphism were also associated with a decreased breast cancer risk in a dominant model in 5,649 cases and 6,856 controls (GG/GC vs. CC: OR, 0.92, 95% CI, 0.85–0.99). These results suggest that potentially functional ESR1 polymorphisms may play a low penetrance role in breast cancer susceptibility. SNPs rs9340799, rs3798577, rs2228480, and rs2077647 in ESR1 were not causative SNPs. SNPs rs2747648, rs1062577, and rs3020314 were recommended in further association studies and functional evaluations.     

BARD1 and breast cancer in Poland

Purpose To investigate whether or not a genetic variant in BARD1 (Cys557Ser) contributes to early-onset breast cancer in Poland, or modifies the risk of breast cancer in women with an inherited predisposition to breast cancer. Experimental design We studied 3,188 unselected Polish women with breast cancer and 1,038 healthy controls. All women were genotyped for the BARD1 Cys557Ser variant and for known founder mutations in BRCA1 (three mutations), CHEK2 (four mutations), and NBS1 (one mutation). Results A BARD1 variant was seen in 150 of 3,188 breast cancer cases (4.7%) and in 40 of 1,038 controls (3.8%) (OR = 1.2; 95% CI = 0.9–1.7). The risk associated with the BARD1 variant was not significantly greater in women with familial cancer (OR = 1.5; 95% CI = 0.8–2.7), or with an inherited mutation in BRCA1 (OR = 0.9; 95% CI = 0.4–2.2), CHEK2 (OR = 1.0; 95% CI = 0.5–2.1), or NBS1 (OR = 1.3; 95% CI = 0.2–10.2). Modest associations were observed among the subgroups of women with very early onset breast cancer (OR = 2.9; 95% CI = 1.2–7.1) and with medullary breast cancer (OR = 1.8; 95% CI = 0.9–3.7). Conclusion There was no clear association between the presence of the BARD1 Cys557Ser allele and breast cancer in Poland. Furthermore, the BARD1 Cys557Ser allele does not appear to modify the risk of breast cancers among carriers of BRCA1 mutations, or of other predisposing mutations. The allele may predispose to breast cancers of certain histologic subtypes, but further studies are needed to confirm these findings.     

RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies

A single-nucleotide polymorphism (SNP) in the 5′-untranslated region (UTR) of RAD51, 135G>C (rs1801320), was reported to be associated with an increased risk of breast cancer among BRCA2 as well as BRCA1 carriers. A few studies have also investigated the genetic contribution of RAD51 135G>C to the risk of sporadic breast cancers or breast cancer in non-BRCA1/2 carriers, though the results are yet controversial and inconclusive. We, in this study, performed a more precise estimation of the relationship between 135G>C and breast cancer among non-BRCA1/2 mutation carriers by meta-analyzing the currently available evidence from the literature. A total of 12 studies involving 7,065 cases and 6,981 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. When all the studies were pooled into the meta-analysis, there was no evidence for a significant association between 135G>C and breast cancer risk in non-BRCA1/2 mutation carriers (for CC vs. GG: OR = 0.995, 95%CI: 0.741–1.336; for GC vs. GG: OR = 0.959, 95%CI: 0.869–1.057; for dominant model: OR = 0.988, 95%CI: 0.902–1.082; and for recessive model: OR = 1.037, 95%CI: 0.782–1.376). We also performed subgroup analysis by ethnicity (Caucasian) as well as did analysis using the studies fulfilling Hardy–Weinberg equilibrium, and the results did not change. In summary, the present meta-analysis suggests that the RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers.     

<Emphasis Type="Italic">GPX1 Pro198Leu</Emphasis> polymorphism and breast cancer risk: a meta-analysis

A genetic polymorphism at codon 198 in the human glutathione peroxidase 1 gene was reported to be associated with several cancers. However, this relationship remains controversial, especially in breast cancer. For better understanding the effect of GPX1 Pro198Leu polymorphism on breast cancer, a meta-analysis was performed. By searching relevant literatures, a total of six case–control studies, containing 5,509 breast cancer cases and 6,542 healthy controls, were included. The strength of association between GPX1 Pro198Leu polymorphism and breast cancer risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95%CI). And the results strongly suggested that there was no significant association between variant Leu allele and breast cancer susceptibility in overall comparisons in all genetic models [additive model: OR, 1.04; 95% CI, 0.92–1.18; P = 0.555; dominant model: OR, 1.01; 95% CI, 0.94–1.09; P = 0.777; recessive model: OR, 1.04; 95% CI, 0.92–1.18; P = 0.536]. However in subgroup analysis, an elevated risk in African population with variant Leu allele was revealed in additive (OR, 1.91; 95% CI, 1.02–3.58; P = 0.044) and recessive (OR, 2.09; 95% CI, 1.16–3.76; P = 0.014) genetic model. No apparent association between this polymorphism and different menopausal status (premenopausal and postmenopausal) and the other ethnicities (almost Caucasians) was showed. In conclusion, this meta-analysis strongly suggests that GPX1 Pro198Leu polymorphism is not associated with breast cancer risk in Caucasians, and an elevated risk in Africans needs large-scale investigations to confirm.     

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.     

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.     

Quantitative assessment of the association between three polymorphisms in FAS and FASL gene and breast cancer risk

FAS and FAS ligand (FASL) play crucial roles in apoptotic signaling, and deregulation of this pathway may facilitate carcinogenesis. Studies on the association between the FAS/FASL polymorphisms (FAS-1377G/A rs2234767, FAS-670A/G rs1800682, and FASL-844C/T rs763110) and breast cancer risk have reported inconsistent results. Therefore, to characterize the relationship between those polymorphisms and breast cancer risk, we undertook a meta-analysis of those studies. Several electronic databases were searched for articles on the FAS/FASL polymorphisms and breast cancer risk. The genotype data were extracted; pooled odds ratios (OR) with 95 % confidence intervals (CIs) were used to estimate the strength of the association. Five studies were eligible for our meta-analysis. Overall, we observed significant associations of the FAS-1377G/A polymorphism with breast cancer susceptibility (AG vs. GG: OR?=?1.15, 95 % CI 1.02–1.30; AA vs. GG: OR?=?1.39, 95 % CI 1.12–1.72; AG/AA vs. GG: OR?=?1.18, 95 % CI, 1.16–1.32; A vs. G: OR?=?1.16, 95 % CI 1.06–1.26), but we did not observe significant association of the Fas-670A/G and FasL-844C/T polymorphisms with breast cancer risk. In the subgroup analysis, we observed that the FAS-1377G/A and FASL-844C/T polymorphisms were associated with breast cancer risk in Chinese but not Whites; we still did not observed association of the FAS-670A/G polymorphism with breast cancer risk. Our meta-analysis revealed that FAS-1377G>A polymorphism was associated with an increased risk of breast cancer. FASL-844C>T polymorphism might be associated with a reduced breast cancer risk in Chinese. However, FAS-670A/G had no any effect on breast carcinogenesis.     

Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis

Prophylactic salpingo-oophorectomy is currently the only effective strategy available for decreasing ovarian cancer risk in BRCA1/2 mutation carriers. Significantly decreased risk of ovarian cancer associated with the use of combined oral contraceptives (COCs) was shown in the general population, which could be an alternative approach for those who do not accept risk-reducing surgery. Cohort, case-control and case-case studies published in English up to December 2009 reporting the association of ovarian or breast cancer risk with the use of COCs and presenting BRCA status were selected for meta-analysis. Meta-analysis of three case-control studies showed a significant risk reduction of ovarian cancer in BRCA1/2 mutation carriers who were associated with any past COC use (odds ratio [OR]: 0.57; 95% CI: 0.47-0.70; p < 0.001) and significant trend by duration of COC use (OR: 0.95; 95% CI: 0.93-0.97; p < 0.001). No significant increase in breast cancer risk associated with COC use has been found in case-control studies in BRCA1 (OR: 1.08; p = 0.250), in BRCA2 (OR: 1.03; p = 0.788) mutation carriers or in case-case studies in BRCA1/2 carriers (OR: 0.80; p = 0.147). Significantly increased risk of breast cancer was only shown on a subset of cohort studies in BRCA1 mutation carriers (OR: 1.48; 95% CI: 1.14-1.92). In conclusion, meta-analysis confirmed significantly decreased ovarian cancer risk in BRCA1/2 mutation carriers associated with the use of COCs comparable to the relative extent shown in the general population. Data on the risk of breast cancer associated with COC use in BRCA mutation carriers are heterogeneous and results are inconsistent. COCs can be considered as an alternative strategy in the chemoprevention of ovarian cancer in BRCA1 mutation carriers who do not accept prophylactic salpingo-oophorectomy above the age of 30 years.     

CD95 rs1800682 polymorphism and cervical cancer risk: evidence from a meta-analysis

CD95 is the first death receptor identified and characterized in recent years, and it plays important roles in the molecular network regulating cell death and survival. CD95 rs1800682 polymorphism is a common genetic polymorphism identified in the CD95 gene. Many publications evaluated the association between CD95 rs1800682 polymorphism and cervical cancer risk, but the association remained inconclusive. To provide a more precise estimate on the association, a meta-analysis was carried out. The association between CD95 rs1800682 polymorphism and cervical cancer risk was assessed by calculating the pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI). On the basis of our inclusion criteria, ten studies with a total of 5,481 individuals were included into the meta-analysis. There was obvious heterogeneity among the included studies. Meta-analysis of the ten studies suggested that there was no association between CD95 rs1800682 polymorphism and cervical cancer risk under all four genetic models (allele model: OR?=?1.05, 95 % CI 0.92–1.18, P?=?0.478; homozygous model: OR?=?1.08, 95 % CI 0.83–1.41, P?=?0.550; dominant model: OR?=?1.12, 95 % CI 0.88–1.42, P?=?0.347; recessive model: OR?=?1.00, 95 % CI 0.76–1.31, P?=?0.978). Subgroup analysis by ethnicity suggested that there was no association between CD95 rs1800682 polymorphism and cervical cancer risk in Asians, Caucasians, and Africans. Thus, the meta-analysis suggests that CD95 rs1800682 polymorphism is not associated with cervical cancer risk.     

Association between tumor necrosis factor-α rs1800629 polymorphism and risk of gastric cancer: a meta-analysis

Gastric cancer is mainly initiated by inflammation and chronic superficial gastritis, and tumor necrosis factor-α (TNF-α) is an inflammatory cytokine which plays an important role in the inflammation. TNF-α rs1800629 G/A polymorphism was proposed to be associated with gastric cancer risk, but previous studies on Caucasians reported conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and gastric cancer risk in Caucasians. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to assess the association. Eleven case–control studies with 7,427 subjects were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with the increased risk of gastric cancer under four genetic comparison models (A versus G: OR?=?1.32, 95 % CI 1.12–1.56, P?=?0.001; AA versus GG: OR?=?1.76, 95 % CI 1.37–2.26, P?<?0.001; AA versus GG/GA: OR?=?1.62, 95 % CI 1.27–2.07, P?<?0.001; AA/GA versus GG: OR?=?1.35, 95 % CI 1.14–1.60, P?=?0.001). Meta-analysis of those studies with high quality showed that TNF-α rs1800629 polymorphism was still significantly associated with the increased risk of gastric cancer under four genetic comparison models. There was no risk of publication bias in the meta-analysis. The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with the increased risk of gastric cancer in Caucasians.     

Association between X-ray repair cross-complementation group 1 rs25487 polymorphism and pancreatic cancer risk

Previous published studies suggested that genetic polymorphisms in DNA repair genes could modify the DNA repair capacity and could be associated with pancreatic cancer risk. However, previous studies on the association between X-ray repair cross-complementation group 1 (XRCC1) rs25487 (Arg399Gln) polymorphism and pancreatic cancer risk reported inconsistent results. To obtain a more precise estimation of the association between XRCC1 rs25487 polymorphism and pancreatic cancer risk, we performed a meta-analysis of previous published studies by calculating the pooled odds ratio (OR) with a 95 % confidence interval (95 % CI). Eight individual studies with 5,542 subjects from six publications were finally included into this meta-analysis. The meta-analysis of total eight studies showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in total population under all four genetic models (Gln versus Arg: OR?=?1.10, 95 % CI 0.95–1.28, P?=?0.199; GlnGln versus ArgArg: OR?=?1.15, 95 % CI 0.93–1.41, P?=?0.191; GlnGln/ArgGln versus ArgArg: OR?=?1.10, 95 % CI 0.97–1.25, P?=?0.127; GlnGln versus ArgArg/ArgGln: OR?=?1.12, 95 % CI 0.92–1.36, P?=?0.253). Subgroup analysis showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in Caucasians, but XRCC1 rs25487 polymorphism was associated with pancreatic cancer risk in Asians (GlnGln/ArgGln versus ArgArg: OR?=?1.24, 95 % CI 1.01–1.53, P?=?0.040). Therefore, the meta-analysis suggests that XRCC1 rs25487 polymorphism is associated with pancreatic cancer risk in Asians. Further studies with more participants are needed to provide a more precise estimation on the association above.     

VEGF 936C>T polymorphism and breast cancer risk: evidence from 5,729 cases and 5,868 controls

Vascular endothelial growth factor (VEGF) is one of the most potent endothelial cell mitogens and plays an important role in angiogenesis. Many published studies have evaluated the association between the VEGF 936C>T polymorphism and breast cancer risk. However, the published findings are inconsistent. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. A total of eight studies including 5,729 breast cancer cases and 5,868 controls were identified. Overall, no significant associations between the VEGF 936C>T polymorphism and breast cancer risk were found for TT versus CC (OR 0.93, 95% CI 0.73–1.19), CT versus CC (OR 0.91, 95% CI 0.77–1.09), TT/CT versus CC (OR 0.92, 95% CI 0.78–1.08), and TT versus CT/CC (OR 0.96, 95% CI 0.75–1.21). In the subgroup analysis by ethnicity, source of controls, and menopausal status, there was still no significant association detected in any of the genetic models. In summary, our results suggest that the VEGF 936C>T polymorphism may not contribute to breast cancer susceptibility.     

<Emphasis Type="Italic">MTRR A66G</Emphasis> polymorphism and breast cancer risk: a meta-analysis

Methionine synthase reductase (MTRR) is one of the important enzymes involved in the folate metabolic pathway and its functional genetic polymorphisms may be associated with breast cancer risk. However, this relationship remains inconclusive. For better understanding the effect of MTRR A66G polymorphism on breast cancer risk, a meta-analysis was performed. By searching PubMed and EMBASE, a total of six case–control studies, containing 6,084 cases and 6,756 controls, were included. The strength of association between MTRR A66G polymorphism and breast cancer risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95% CI). The results strongly suggested that there was no significant association between MTRR A66G polymorphism and breast cancer susceptibility in overall comparisons in all genetic models (additive model: OR 1.00, 95% CI 0.89–1.11, P = 0.943; dominant model: OR 1.00, 95% CI 0.91–1.10, P = 0.989; recessive model: OR 1.00, 95% CI 0.91–1.09, P = 0.926). Similarly, in subgroup analyses for ethnicity (Caucasian, Asian and mixed population) and folate intake status (high and low folate intake), the results were negative. Sensitivity analysis demonstrated that omitting any study did not perturb the results. In conclusion, this meta-analysis strongly suggests that MTRR A66G polymorphism is not associated with breast cancer risk, especially in Caucasians and Asians.     

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.