A <Emphasis Type="Italic">CYP19</Emphasis> (aromatase) polymorphism is associated with increased premenopausal breast cancer risk

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20–2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74–8.70] and OR = 2.52 [1.26–5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82–1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.     

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.     

Active and passive smoking, <Emphasis Type="Italic">IL6</Emphasis>, <Emphasis Type="Italic">ESR1</Emphasis>, and breast cancer risk

We evaluated the association between smoking and risk of breast cancer in non-Hispanic white (NHW) and Hispanic or American Indian (HAI) women living in the Southwestern United States. Data on lifetime exposure to active and passive smoke data were available from 1527 NHW cases and 1601 NHW controls; 798 HAI cases and 924 HAI controls. Interleukin 6 (IL6) and Estrogen Receptor alpha (ESR1) polymorphisms were assessed in conjunction with smoking. Pack-years of smoking (≥15) were associated with increased risk of pre-menopausal breast cancer among NHW women (OR 1.6, 95% CI 1.1–2. 4). Passive smoke increased risk of pre-menopausal breast cancer for HAI women (OR 1.9, 95% CI 1.1–3.1 everyone; OR 2.3, 95% CI 1.2–4.5 nonsmokers). HAI pre-menopausal women who were exposed to 10+ h of passive smoke per week and had the rs2069832 IL6 GG genotype had over a fourfold increased risk of breast cancer (OR 4.4, 95% CI 1.5–12.8; P for interaction 0.01). Those with the ESR1 Xba1 AA genotype had a threefold increased risk of breast cancer if they smoked ≥15 pack-years relative to non-smokers (P interaction 0.01). These data suggest that breast cancer risk is associated with active and passive smoking.     

<Emphasis Type="Italic">HER2</Emphasis> codon 655 polymorphism and breast cancer risk: a meta-analysis

To evaluate the association between HER2 codon 655 polymorphism and breast cancer risk in this meta-analysis. A comprehensive search was performed to identify all case–control studies investigating such association. Statistical analyses were conducted with software MIX 1.54. Twenty eligible reports, including 10,642 cases/11,259 controls, were identified. In overall analysis, the Val allele frequency in cases was significantly higher than that in controls (OR = 1.0921, 95% CI: 1.0013–1.191, P = 0.0466), while no associations were found in both recessive and dominant models. In subgroup analysis, HER2 codon 655 polymorphism was weakly associated with breast cancer risk in recessive (OR = 2.4624, 95% CI: 1.0619–5.7104, P = 0.0357), dominant (OR = 1.2781, 95% CI: 1.0353–1.5779, P = 0.0225), and co-dominant genetic models (OR = 1.2947, 95% CI: 1.0682–1.5693, P = 0.0085) in Asian population, respectively. Meanwhile, the susceptibility to breast cancer in people aged ≤45 was significantly increased in both recessive (OR = 2.2408; 95% CI: 1.2876–3.8998, P = 0.0043), and dominant models (OR = 1.2902, 95% CI: 1.1035–1.5085, P = 0.0014). No significant associations were observed in Caucasian, European, and Family history subgroups. So our analyses suggest HER2 codon 655 Val allele is weakly associated with an increased risk of breast cancer, and SNP at HER2 codon 655 could be considered as a susceptibility biomarker for breast cancer for Asian females or women age 45 years or younger. Weiyang Tao and Chunyang Wang contribute equally to this work.     

Polymorphisms in three obesity-related genes (<Emphasis Type="Italic">LEP</Emphasis>, <Emphasis Type="Italic">LEPR</Emphasis>, and <Emphasis Type="Italic">PON1</Emphasis>) and breast cancer risk: a meta-analysis

Common genetic variations in the leptin (LEP), leptin receptor (LEPR), and paraoxonase 1 (PON1) genes have been considered to be implicated in the development of breast cancer. However, the results were inconsistent. In this study, a meta-analysis was performed to assess the associations of five polymorphisms, including LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, and PON1 Q192R polymorphisms, with breast cancer risk. Published literature from PubMed, ISI Web of Science, Embase databases, CNKI, and Wanfang Data were retrieved. All studies evaluating the association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, or PON1 Q192R polymorphism and breast cancer risk were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Three studies (2,003 cases and 1,967 controls) for LEP G2548A polymorphism, nine studies (4,627 cases and 5,476 controls) for LEPR Q223R polymorphism, five studies (2,759 cases and 2,573 controls) for LEPR Lys109Arg polymorphism, four studies (1,517 cases and 1,379 controls) for PON1 L55M polymorphism, and five studies (1,575 cases and 2,283 controls) for PON1 Q192R polymorphism were included in the meta-analysis. Overall, the results showed null significant association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, or PON1 Q192R polymorphism and breast cancer risk; however, PON1 L55M was significantly associated with breast cancer risk overall (MM vs. LL: OR = 2.16; 95% CI, 1.76–2.66). For LEPR Q223R polymorphism, further subgroup analysis suggested that the association was only statistically significant in East Asians (OR = 0.50; 95% CI, 0.36–0.70) but not in Caucasians (OR = 1.06; 95% CI, 0.77–1.45) or Africans (OR = 1.30; 95% CI, 0.83–2.03). The present meta-analysis suggested that LEPR Q223R polymorphism might be implicated in the development of breast cancer in East Asians; PON1 L55M might increase breast cancer risk. However, given the limited sample size, the findings warrant further investigation.     

The <Emphasis Type="Italic">TGFBR1</Emphasis>*6A/9A polymorphism is not associated with differential risk of breast cancer

A polymorphic 9-bp deletion in exon 1 of TGFBR1 (TGFBR1*6A) has been identified as a low-penetrance cancer susceptibility allele. The strongest association in the initial studies was with breast cancer; however, these studies included patients with different types of cancer, including colon, cervical and breast carcinomas, with only a small proportion being breast cancer patients. In subsequent case–control studies focussing on breast cancer alone, the results have been equivocal. In order to clarify whether TGFBR1*6A is associated with breast cancer risk, we have genotyped this polymorphism in 988 breast cancer cases and 1,016 controls from the West of Ireland and also performed a meta-analysis of previously published data (5,150 cases and 6,344 controls). In our series from the West of Ireland, we found no association (genotypic odds ratio (OR) under a dominant model = 0.93, 95% confidence interval (CI) 0.73–1.19, P = 0.57; allelic OR = 0.93, 95% CI 0.74–1.15, P = 0.49). Meta-analysis showed evidence of heterogeneity among studies. Using the random effects model, it was found that there was no evidence of an association of the *6A allele with breast cancer (genotypic OR under a dominant model = 1.10, 95% CI = 0.94–1.28, P = 0.24, allelic OR = 1.12, 95% CI 0.97–1.31, P = 0.13). In conclusion, our study shows that there is no association between TGFBR1*6A and breast cancer risk.     

<Emphasis Type="Italic">CCND1</Emphasis> G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis

Cyclin D1 (CCND1), a key cell cycle regulatory protein that governs the cell cycle progression from G1 to S phase, can promote cell proliferation or induce growth arrest and apoptosis. Since the identification of a well-characterized functional polymorphism, G870A in exon 4 of CCND1, several molecular epidemiological studies were conducted in recent years to evaluate the association between G870A and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 5,371 cases with breast cancer and 5,336 controls from 7 published case-control studies showed that the variant allele 870A was associated with a significantly increased risk of breast cancer (AA vs. GG: OR = 1.18, 95% CI = 1.06–1.32; AG vs. GG: OR = 1.12, 95% CI = 1.01–1.23; AA/AG vs. GG: OR = 1.14, 95% CI = 1.04–1.25) without any between-study heterogeneity. In the stratified analysis by race, we found that the increased breast cancer risk associated with G870A polymorphism was more evident in Caucasians (OR = 1.14, 95% CI = 1.01–1.28, P = 0.88 for heterogeneity test), but not significant in Asians (OR = 1.10, 95% CI = 0.85–1.42, P = 0.05 for heterogeneity test). The results suggest that CCND1 G870A polymorphism may contribute to breast cancer development, especially in Caucasians. Additional well-designed large studies were required for the validation of this association in different populations. Cheng Lu and Jing Dong contributed equally to this work.     

Three common <Emphasis Type="Italic">TP53</Emphasis> polymorphisms in susceptibility to breast cancer,evidence from meta-analysis

The association of polymorphisms of tumor suppressor gene TP53 with breast cancer has widely been reported; however, the results are inconsistent. Here, we selected three commonly studied TP53 polymorphisms: codon 72 Arg > Pro, IVS3 16 bp Del/Ins, and IVS6 + 62A > G to explore their association with breast cancer risk by meta-analysis of published case–control studies. The results showed that codon 72 was not associated with breast cancer risk among 37 combined case–control studies (23,567 cases and 25,995 controls). However, a significant association with decreased risk of breast cancer was found in the Mediterranean studies (PP + PR vs. RR: OR = 0.32, 95% CI = 0.24−0.44, P < 0.001; PP vs. RR: OR = 0.35, 95% CI = 0.21−0.60, P < 0.001). IVS3 16 bp Del/Ins was significantly associated with an increased risk of developing breast cancer in a pooled 8 study dataset (2,470 cases and 2,825 controls; Ins/Ins + Del/Ins vs. Del/Del: OR = 1.15, 95% CI = 1.01−1.30, P = 0.04; Ins/Ins vs. Del/Del: OR = 1.75, 95% CI = 1.20−2.37, P = 0.003). No significant association was observed between IVS6 + 62A > G and breast cancer risk in a total of 10 studies (8,537 cases and 9,586 controls). These results suggest that IVS3 16 bp Del/Ins is likely an important genetic marker contributing to susceptibility of breast cancer, and codon 72 has a potential role in association with breast cancer risk within certain populations or regions.     

Association between <Emphasis Type="Italic">EGF</Emphasis> promoter polymorphisms and cancer risk: a meta-analysis

EGF promoter polymorphisms are observed to modulate EGF levels and thought to have effect on susceptibility to various carcinomas but the results are inconsistent. In this meta-analysis, we assessed published studies of the association between three EGF polymorphisms and cancer risk from 21 studies with 14,609 subjects for EGF G61A, from two studies with 2,535 subjects for G-1380A and A-1744G, respectively. For EGF G61A, the contrast of homozygote (OR = 0.80, 95% CI = 0.65–0.98), allele (OR = 0.90, 95% CI = 0.81–0.99) and dominant model (OR = 0.86, 95% CI = 0.74–0.99) produced significant association among 21 studies with relatively large heterogeneity (P _{heterogeneity} < 0.001). Through the stratified analysis, heterogeneity decreased significantly. In the stratified analysis by racial descent, the significant risks were found among Asians for homozygote contrast (OR = 0.83, 95% CI = 0.69–0.99, P _{heterogeneity} = 0.506) and Americans for the contrast of homozygote (OR = 0.50, 95% CI = 0.30–0.84, P _{heterogeneity} = 0.051), allele (OR = 0.70, 95% CI = 0.51–0.96, P _{heterogeneity} = 0.008) and dominant model (OR = 0.57, 95% CI = 0.42–0.77, P _{heterogeneity} = 0.28). No significant associations were found in all Caucasians genetic models. In the subgroup analyses by cancer types, for gastric cancer and esophageal cancer significant associations were found in all genetic models without heterogeneity. Significant risk was also found in the contrast of homozygote (OR = 0.41, 95% CI = 0.20–0.81, P _{heterogeneity} = 0.184) and recessive model (OR = 0.53, 95% CI = 0.33–0.85, P _{heterogeneity} = 0.384) for hepatoma and recessive model (OR = 0.72, 95% CI = 0.53–0.99, P _{heterogeneity} = 0.474) for glioma. For EGF G-1380A and A-1744G, no significant associations were found in all genetic models. This meta-analysis suggests that the EGF G61A polymorphism most likely contributes to decreased susceptibility to cancers among Asians and Americans, and A allele may be a protective factor for gastric cancer, esophageal cancer, hepatoma and glioma. Both EGF G-1380A and A-1744G is marginally associated with cancer susceptibility.     

<Emphasis Type="Italic">TP53</Emphasis> Arg72Pro polymorphism and endometrial cancer risk: a meta-analysis

Studies investigating the relationship between TP53 Arg72Pro polymorphism and endometrial cancer risk reported conflicting results. To explore a more precise estimate of the effect of this polymorphism on endometrial carcinogenesis, a meta-analysis was performed by searching eligible studies in PubMed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association for codominant model (Arg/Arg vs. Pro/Pro, Arg/Pro vs. Pro/Pro), dominant model (Arg/Arg + Arg/Pro vs. Pro/Pro), and recessive model (Arg/Arg vs. Arg/Pro + Pro/Pro), respectively. Subgroup analyses were performed by Hardy–Weinberg equilibrium (HWE) in controls, the specimen of cases for determining TP53 genotypes, sample size, the source of control and case groups, and ethnicity. We identified 8 case–control studies involving 2,154 subjects for this meta-analysis. Overall, no evidence of association was observed between TP53 genotypes and endometrial cancer risk in all genetic models (Arg/Arg vs. Pro/Pro: OR = 0.98, 95% CI: 0.69–1.39, P = 0.90; Arg/Pro vs. Pro/Pro: OR = 1.00, 95% CI: 0.71–1.42, P = 0.98; dominant model: OR = 0.99, 95% CI: 0.71–1.38, P = 0.95; recessive model: OR = 1.06, 95% CI: 0.80–1.41, P = 0.95). Stratified analyses also detected no significant association in any subgroup, except among those studies with controls deviated from HWE in recessive model (OR = 1.60, 95% CI: 1.07–2.39). In conclusion, we did not observe any evidence for a role of TP53 Arg72Pro polymorphism in endometrial cancer. The reported significant association between this polymorphism and endometrial cancer risk may be due to methodological errors such as selection bias, small sample size, Type I error, and population stratification.     

Genetic variations in transcription factor 7-like 2 (<Emphasis Type="Italic">TCF7L2)</Emphasis> gene: association of <Emphasis Type="Italic">TCF7L2</Emphasis> rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters

The purpose of the present study was to evaluate the association between TCF7L2 rs12255372(G/T) or rs7903146(C/T) polymorphism and breast cancer risk, and clinico-pathologic characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method in a hospital-based Malaysian population. The allele (P = 0.033) frequency of rs7903146 (T) polymorphism was significantly higher in the cancer patients than normal individuals. No significant association was demonstrated between CT (OR^adj = 1.386; 95% CI, 0.985–1.949) or TT (OR^adj = 1.579; 95% CI, 0.869–2.870) genotype and breast cancer risk. However, women who were carriers of T allele (OR^adj = 1.316; 95% CI, 1.022–1.695) or T allele genotype (OR^adj = 1.419; 95% CI, 1.027–1.960) showed significant increased risk of breast cancer. Women who were GT heterozygotes (OR^adj = 1.329; 95% CI, 0.948–1.862) or TT homozygotes (OR^adj = 1.574; 95% CI, 0.829–2.987), and carriers of T allele genotype (OR^adj = 1.365; 95% CI, 0.989–1.883) or T allele (OR^adj = 1.284; 95% CI, 0.995–1.657) were not associated with breast cancer risk. The rs7903146(T) allele genotype was significantly associated with nodal involvement (P = 0.003) but rs12255372 (T) allele genotype was not associated with the clinico-pathologic characteristics. In conclusion, our findings suggest that rs7903146 (T) variant may elevate the risk of breast cancer, thus could be a potential candidate for breast cancer susceptibility. The variant may also increase the metastatic potential of the tumor.     

Genetic variation in <Emphasis Type="Italic">IGF1</Emphasis>, <Emphasis Type="Italic">IGFBP3</Emphasis>, <Emphasis Type="Italic">IRS1</Emphasis>, <Emphasis Type="Italic">IRS2</Emphasis> and risk of breast cancer in women living in Southwestern United States

Background An insulin-related pathway to breast cancer has been hypothesized. Methods We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah. Results Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21–3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13–6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06–2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47–0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones. Conclusions Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.     

<Emphasis Type="Italic">MDM2</Emphasis> 309 T/G polymorphism is associated with colorectal cancer risk especially in Asians: a meta-analysis

The murine double minute 2 (MDM2) gene encodes an important regulator which mainly functions as an E3 ligase. The role of the MDM2 protein in the P53 pathway has been especially well-studied. In this study, our aim was to explore the relationship between MDM2 gene 309 T/G polymorphism and colorectal cancer risk. Performing both the overall meta-analysis and the subgroup meta-analysis based on ethnicity and source of controls with a total of 7 eligible studies (2,543 cases and 2,115 controls in all), we detected a significant colorectal cancer risk variation for TG versus GG (OR = 0.73, 95% CI = 0.62–0.86) in the overall analysis and another significant colorectal cancer risk variation for TG versus GG (OR = 0.70, 95% CI = 0.59–0.83) in the population-based controls’ subgroup as well. Moreover, in the subgroup analysis based on ethnicity, significant associations were observed for all genetic models in Asians (OR = 0.51, 95% CI = 0.41–0.64 for TT versus GG; OR = 0.64, 95% CI = 0.53–0.78 for TG versus GG; OR = 0.59, 95% CI = 0.49–0.71 for dominant model; OR = 0.69, 95% CI = 0.57–0.82 for recessive model), while in Caucasians there was no obvious association. In summary, according to the results of our meta-analysis, the MDM2 309 G allele probably acts as a colorectal cancer risk factor, especially in Asians.     

<Emphasis Type="Italic">CHEK2</Emphasis> 1100delC and male breast cancer in the Netherlands

Mutations in the breast cancer susceptibility genes BRCA1, BRCA2, and CHEK2 are known risk factors for female breast cancer. Mutations in BRCA1 and BRCA2 also are associated with male breast cancer (MBC). Similarly, it had been suggested in the original CHEK2 identification report that the CHEK2 1100delC mutation confers an increased risk for MBC. Here, we have evaluated the risk of CHEK2 1100delC for MBC by genotyping CHEK2 1100delC in 23 familial and 71 unselected Dutch MBC cases. None of the 23 familial MBC cases carried the CHEK2 1100delC mutation. In contrast, CHEK2 1100delC was present in 3 of the 71 (4.2%) unselected MBC cases, which was significantly more prevalent than the 1.1% Dutch population frequency assessed in 1,692 individuals (P = 0.05, OR = 4.1, 95% CI 1.2–14.3). Our data suggest that, in the Netherlands, CHEK2 1100delC is associated with an increased risk for MBC.     

Variation in the <Emphasis Type="Italic">CYP19A1</Emphasis> gene and risk of colon and rectal cancer

CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case–control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16–1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50–0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26–2.37). We observed statistically significant interactions between genetic variation in NFκB1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism.     

Polymorphisms of the NER pathway genes, <Emphasis Type="Italic">ERCC1</Emphasis> and <Emphasis Type="Italic">XPD</Emphasis> are associated with esophageal adenocarcinoma risk

Purpose  Functional variation in DNA repair capacity through single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer. Studies have focused on the nucleotide excision repair (NER) and base excision repair (BER) pathways. We investigated whether variant alleles in seven SNPs within these pathways increased the risk of esophageal adenocarcinoma. Methods  DNA was extracted from prospectively collected blood specimens. The samples were genotyped for SNPs in NER genes (XPD Lys751Gln, XPD Asp312Asn, ERCC1 8092C/A, and ERCC1 118C/T), and BER genes (XRCC1 Arg399Gln, APE1 Asp148Glu, and hOGG1 Ser326Cys). The presence of variant alleles was correlated with risk of esophageal adenocarcinoma both individually and jointly. Results  Variant alleles in NER SNPs XPD Lys751Gln (AOR = 1.50, 95% CI 1.1–2.0), ERCC1 8092 C/A (AOR = 1.44, 95% CI 1.1–1.9), and ERCC1 118C/T (AOR = 1.42, 95% CI 1.0–1.9) were individually associated with esophageal adenocarcinoma risk. An increasing number of variant alleles in NER SNPs showed a significant trend with esophageal adenocarcinoma risk (p = 0.007). Conclusions  The presence of variant alleles in NER genes increases risk of esophageal adenocarcinoma. There is evidence of an additive role for SNPs along a common DNA repair pathway. Future larger studies of esophageal adenocarcinoma etiology should evaluate entire biological pathways.     

Prophylactic Mastectomy and Risk-Reducing Salpingo-oophorectomy in <Emphasis Type="Italic">BRCA1/2</Emphasis> Mutation Carriers

Women with either BRCA1 or BRCA2 germline mutations have a significantly elevated risk of breast and ovarian cancer. Approximately 60 %–70 % of BRCA1 carriers and 45 %–60 % of BRCA2 carriers will develop a breast cancer by age 70, and there is a lower but very significant risk of developing ovarian cancer in both BRCA1 and BRCA2 carriers. This review summarizes data from both retrospective and prospective studies examining the impact of bilateral prophylactic mastectomy and risk-reducing salpingo-oophorectomy on reducing the risk of developing breast and, for the latter, ovarian cancer. In addition, we review data on the mortality benefit from risk-reducing salpino-oophorectomy.     

Penetrance of breast cancer,ovarian cancer and contralateral breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> families: high cancer incidence at older age

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2–82.4%) in BRCA1 and 87.5% (82.4–92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5–64.3%) in BRCA1 and 34.5% (25.0–44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4–39.0%) in BRCA1 families and 29.2% (22.9–35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.     

Relationship between <Emphasis Type="Italic">XRCC3</Emphasis> T241M polymorphism and gastric cancer risk: a meta-analysis

The X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3) gene is a member of the RAD51 gene family. It encodes an important protein that functions in the homologous recombination repair of DNA double-strand break. In this study, our aim was to explore the relationship between XRCC3 T241M polymorphism and gastric cancer risk. Performing both the overall meta-analysis and subgroup meta-analysis based on ethnicity, source of controls, and cancer location with a total of 6 eligible studies (1,154 cases and 1,487 controls in all), we detected no significant gastric cancer risk variation for all genetic models in the overall analysis and in the subgroup analysis based on cancer location. What is interesting is in the subgroup analysis based on ethnicity, where significantly decreased gastric cancer risk was observed for recessive model in Asians (OR = 0.69, 95% CI = 0.50–0.95), while significantly increased gastric cancer risk was detected for dominant model in Caucasians (OR = 1.45, 95% CI = 1.01–2.08). In summary, according to the results of our meta-analysis, the XRCC3 T241M polymorphism might influence gastric cancer risk oppositely in Asians and Caucasians.     

<Emphasis Type="Italic">NBS1</Emphasis> variant I171V and breast cancer risk

The NBS1/p95 protein has a pivotal role in the sensing and repair of chromosome breaks. A missense mutation in the NBS1 gene, I171V, has recently been associated with a ninefold increased risk of breast cancer in Polish patients. Positive associations have also been reported for leukaemia and larynx cancer suggesting that I171V could be a more general susceptibility factor for malignancies. We investigated the prevalence of this mutation in two large hospital-based case-control series from Germany and from the Republic of Belarus. The I171V substitution was detected in 20/1,636 Byelorussian breast cancer patients and in 18/1,014 Byelorussian controls (OR: 0.68; 95%CI: 0.36–1.30, P = 0.3). The I171V substitution was furthermore detected in 10/1,048 German breast cancer patients and in 7/1,017 German controls (OR: 1.39; 95%CI: 0.53–3.67, P = 0.7). There were no significant differences between I171V carriers and non-carriers among the cases with regard to age at diagnosis, family history or bilateral occurrence of disease. A meta-analysis of all hitherto available studies did not reveal a difference in the prevalence of I171V between breast cancer cases and controls (OR: 1.05; 95%CI: 0.64–1.74, P = 0.9). We conclude that the I171V substitution is unlikely to constitute a strong risk factor for breast cancer in our study populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.