Nucleotide excision repair gene ERCC1 polymorphisms contribute to cancer susceptibility: a meta-analysis

Individual studies of the associations between excision repair cross-complimentary group 1 (ERCC1) polymorphisms and cancer susceptibility have shown inconclusive results. To derive a more precise estimation of the relationship between three well-characterised polymorphisms on ERCC1 and the risk of cancer, we performed a meta-analysis based on 48 publications. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the associations. We found that ERCC1 17677A (rs3212961) variant genotypes were associated with significantly increased overall risk of cancer without substantial heterogeneity (AA versus CC, OR = 1.36, 95% CIs: 1.10-1.68; AC versus CC: OR = 1.11, 95% CIs: 0.99-1.26; dominant comparison: AA/AC versus CC: OR = 1.15, 95% CIs: 1.02-1.29; recessive comparison: AA versus AC/CC: OR = 1.25, 95% CIs: 1.05-1.49). The ERCC1 19007 C (rs11615) allele had null effects on overall risk of cancer; but in the stratified analyses, we observed an elevated association in Asian populations with homozygote variants and hospital-based controls. In addition, during further stratified analyses of cancer groups, homozygote variants were found that are associated with lung cancer and smoking-related cancers. Also, the observed ERCC1 19007 C heterozygote variant contributes to the development of skin cancer. However, the ERCC1 8092C > A (rs3212986) polymorphism did not appear to have an effect on cancer risk. Additionally, no evidence of publication bias was observed in these polymorphisms. Our meta-analysis supports the conclusion that the ERCC1 17677A > C and ERCC1 19007T > C polymorphisms, but not the ERCC1 8092C > A polymorphism, are low-penetrance risk factors for cancer development.     

Association of ERCC gene polymorphism with osteosarcoma risk

BackgroundThe relationship between ERCC gene polymorphism and osteosarcoma risk / overall survival of osteosarcoma is still conflicting, and this meta-analysis was performed to assess these associations.Material and methodsThe association studies were identified from PubMed, and eligible reports were included and calculated using meta-analysis method.ResultsFour studies were included for the association of ERCC gene polymorphism with osteosarcoma risk, and nine studies were recruited into this meta-analysis for the relationship between ERCC gene polymorphism and overall survival of osteosarcoma. The meta-analysis indicated that ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (A>G) gene polymorphism, ERCC2 rs13181 (Lys751Gln) gene polymorphism were not associated with osteosarcoma risk. ERCC1 rs2298881 (C>A) gene polymorphism, ERCC1 rs3212986 (8092 C>A) gene polymorphism, ERCC1 rs11615 (19007 T>C) gene polymorphism, ERCC2 rs1799793 (Asp312Asn) gene polymorphism were not associated with overall survival of osteosarcoma. Interestingly, ERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma, but AA genotype not (A allele: OR = 0.78, 95% CI: 0.65–0.93, P = 0.007; GG genotype: OR = 1.32, 95% CI: 1.05–1.65, P = 0.02; AA genotype: OR = 0.69, 95% CI: 0.45–1.04, P = 0.08).ConclusionERCC2 rs13181 A allele and GG genotype were associated with overall survival of osteosarcoma.     

The E-cadherin (CDH1)--160 C/A polymorphism and prostate cancer risk: a meta-analysis

Published data on the association between E-cadherin (CDH1) -160 C/A polymorphism and prostate cancer (PCA) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A logistic regression approach proposed for molecular association studies was used to estimate a biological model of the gene effect. A total of 11 studies including 2637 cases and 2673 controls were involved in this meta-analysis. Logistic regression analysis indicated that the CDH1 -160 C/A genotypes were associated with PCA risk. The genetic model test indicated that the genetic model was most likely to be dominant (CA+AA vs CC). Overall, meta-analysis indicated that the -160A allele carriers (CA+AA) had a 21% elevated risk of PCA, when compared with the homozygotes (CC) (odds ratio (OR)=1.21; 95% confidence interval (CI): 0.97-1.51; P=0.090, P(heterogeneity)=0.001). In the subgroup analyses by ethnicity, significantly elevated risks were associated with -160 variant genotypes (CA+AA) in both European and Asian populations (OR=1.24; 95% CI: 1.08-1.43; P=0.003, P(heterogeneity)=0.220 and OR=1.54; 95% CI: 1.23-1.93; P<0.001, P(heterogeneity)=0.200). However, no significant associations were found in Africans (OR=0.59; 95% CI: 0.32-1.09; P=0.090, P(heterogeneity)=0.070). Although some modest bias could not be eliminated, this meta-analysis suggests that the CDH1 -160A allele is a low-penetrant risk factor for developing PCA, especially in Europeans and Asians.     

Lack of association between DNA repair gene ERCC1 polymorphism and risk of lung cancer in a Chinese population

The ERCC1 (Excision Repair Cross Complementation Group 1) gene is involved in the nucleotide excision repair pathway. This study was designed to examine whether ERCC1 Asn118Asn (G19007A) polymorphism, which has been associated with risk of some cancers among Caucasians, may be associated with risk of lung cancer in a Chinese population. ERCC1 Asn118Asn (G19007A) genotypes were determined in DNA samples from 151 cases and 143 controls. The distribution of genotypes between cases and controls was not associated with an increased risk of lung cancer (AA versus GG: adjusted OR (odds ratio) = 1.41, 95% CI (confidence interval) = 0.76-2.59; AG versus GG: adjusted OR = 0.78, 95% CI = 0.47-1.29; and AA + AG versus GG: adjusted OR = 0.93, 95% CI = 0.73-1.19). The frequency A (0.20) of the A-allele was significantly lower among these Chinese controls than in the Caucasian control populations (A = 0.54-0.65) (All P < 0.001). No statistically significant effects of age, histological subtype or smoking were found. These findings suggest that ERCC1 Asn118Asn (G19007A) polymorphism may play a limited role for lung cancer in this Chinese population.     

Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis

Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls) showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval (CI) 0.89–0.98, P=0.22 (for heterogeneity)] for a worldwide population. Meta-analyses of other genetic contrasts suggested that the 677T allele is more likely to affect CRC in a recessive genetic model worldwide (P<0.0001, OR=0.86; 95% CI 0.76–0.96, P=0.06) and in Asians (P=0.0005, OR=0.75; 95% CI 0.64–0.88, P=0.71). Similarly, we found a significantly decreased risk of CRC for 1298C polymorphism (4,764 CRC patients and 6,592 controls) for a recessive genetic model worldwide (P=0.005, OR=0.81; 95% CI 0.70–0.94, P=0.40) and in Caucasians (P=0.04, OR=0.75 95% CI 0.57–0.99, P=0.35). No evidence of association of C677T (4,616 patients and 6,338 controls) and A1298C (1,272 patients and 1,684 controls) with colorectal adenoma were found. The evidence accumulated suggests that MTHFR may represent a low-penetrance susceptible gene for CRC, and that the two polymorphisms might protect against colorectal adenoma developing into cancer. A larger single study is required to further evaluate gene–gene and gene–environment interactions for MTHFR polymorphisms and the cancer risk in a specific population. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis

To clarify the influence of MTHFR C677T and A1298C polymorphisms on gastric cancer (GC), a meta-analysis of eight case-control studies (1,584/2,785 cases/controls) was carried out. Overall, there was moderate heterogeneity among studies, and the C677T allele T was associated with a 27% increased risk of GC compared with C allele: the random effects (RE) OR (95% confidence interval in parenthesis) was significant [OR=1.27 (1.13–1.44)]. In East Asians, the association was significant: RE OR=1.28 (1.14–1.44), whereas, in Caucasians it was not significant. Regarding gastric cancer adenocarcinoma (GCA), an association for the allele contrast in East Asians was detected: fixed effects (FE) OR=1.36 (1.18–1.56). The recessive model for allele T produced significant results overall and in East Asians for GC [FE OR=1.47 (1.26–1.72) and FE OR=1.61 (1.32–1.96), respectively] and for GCA [RE OR=1.53 (1.13–2.05) and FE OR=1.70 (1.36–2.12)]. The A1298C polymorphism was associated with GCA in East Asians: the FE OR for the allele contrast (C vs. A) was 1.38 (1.18–1.62), and under a recessive model for allele C, OR=1.62 (1.28–2.06). There were no sources of bias in the selected studies; the differential magnitude of effect in large versus small studies was not significant. In conclusion, there is evidence of association between MTHFR polymorphisms and GC, mainly in East Asians.     

A meta-analysis on XRCC1 R399Q and R194W polymorphisms, smoking and bladder cancer risk

To elucidate the role of X-ray repair cross-complementing group 1 (XRCC1) R399Q and R194W genotypes in bladder cancer risk, all available studies were considered in the present meta-analysis, with 4152 patients and 5372 controls for R399Q and 3215 patients and 4313 controls for R194W. Studies were identified in PubMed up to June 2008. Overall, the 399Q allele showed no significant effect on bladder cancer compared to 399R allele in all subjects. Insignificant association between R399Q and bladder cancer was observed under other genetic contrasts in worldwide population, Caucasians and never-smokers. Among ever-smokers, protective effects of 399QQ genotype were observed under recessive model [P = 0.004, fixed-effects (FEs) model odds ratio (OR) = 0.65; 95% confidence interval (CI) (0.49, 0.86), I(2) = 0% P(heterogeneity) = 0.57] and homozygote contrast (P = 0.01, FE OR = 0.66; 95% CI (0.49, 0.90), I(2) = 0%, P(heterogeneity) = 0.76). No apparent effect of 194W allele compared to 194R on bladder cancer risk was found in all subjects and Caucasians. It indicated that XRCC1 R399Q and R194W might not be risk factors to bladder cancer, but the 399QQ genotype decreased susceptibility of bladder cancer under recessive model and homozygote contrast among ever-smokers. Further studies based on larger, stratified population were required to explore the role of XRCC1 polymorphisms in bladder cancer risk.     

A meta-analysis of DNA repair gene <Emphasis Type="Italic">XPC</Emphasis> polymorphisms and cancer risk

Polymorphisms (A33512C, C21151T and PAT −/+) of the xeroderma pigmentosum group C (XPC) were shown to contribute to genetic susceptibility to cancer. However, association studies on these polymorphisms in cancer have shown conflicting results. Thus, we performed a meta-analysis. Overall, there was no significant association between 33512C (9,091 patients and 11,553 controls) and cancer risk. No significant association was found in stratification analysis by tumor sites and ethnicities except an elevated lung cancer risk under the recessive genetic model in all subjects [P = 0.04, odds ratio (OR) = 1.20, 95% confidence interval (CI) 1.00–1.45, P _{heterogeneity} = 0.88]. There was no significant association between 21151T (5,227 patients and 5,959 controls) and cancer risk in all subjects but an increased cancer risk in Caucasians under the recessive genetic model (P = 0.006, OR = 1.45, 95% CI 1.11–1.90, P _{heterogeneity} = 0.75) and homozygote comparison (P = 0.02, OR = 1.41, 95% CI 1.07–1.81, P _{heterogeneity} = 0.41). It might be that 21151T increases bladder cancer risk under the recessive genetic model (P = 0.02, OR = 1.49, 95% CI 1.06–2.09, P _{heterogeneity} = 0.47) and homozygote comparison (P = 0.02, OR = 1.49, 95% CI 1.05–2.11, P _{heterogeneity} = 0.23). There was no significant association between PAT + (4,600 patients and 4,866 controls) and cancer risk in all subjects. An increased cancer risk in Caucasians was found under the recessive genetic model (P = 0.02, OR = 1.20, 95% CI 1.03–1.40, P _{heterogeneity} = 0.37) and homozygote comparison (P = 0.008, OR = 1.26, 95% CI 1.06–1.50, P _{heterogeneity} = 0.13). The XPC PAT + allele might increase head and neck cancer risk (P = 0.02, OR = 1.29, 95% CI 1.04–1.59, P _{heterogeneity} = 0.15). More studies based on larger, stratified, case–control population, especially studies investigate the combined effect of XPC A33512C, C21151T, and PAT, are required to further evaluate the role of these polymorphisms in different cancers.     

Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer

The steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) gene plays a crucial role in androgen metabolism pathway in human prostate. It encodes SRD5A2 enzyme, which catalyses testosterone to dihydrotestosterone (DHT). DHT is the main active structure binding with androgen receptor (AR). After the activation of AR, it further regulates a series of target genes in androgen metabolism pathway. However, no clear consensus has been reached on the association between the SRD5A2 V89L, A49T and TA repeat polymorphisms and prostate cancer (PCa) risk. Thus, we performed a meta-analysis of 31 association studies with 14,726 PCa cases and 15,802 controls. We found no association between PCa and 89L compared with 89V allele [odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.98-1.06, P(heterogeneity) = 0.44]. The 49T allele showed a significantly elevated effect on the high stage (Stages III-IV) of PCa risk both under the dominant genetic model (OR = 2.13, 95% CI 1.44-3.15, P(heterogeneity) = 0.65) and in the contrast T versus A allele (OR = 2.06, 95% CI 1.41-3.02, P(heterogeneity) = 0.69). There was a significantly decreased association between PCa and long TA repeat as compared versus short TA repeat (OR = 0.86, 95% CI 0.74-1.00, P(heterogeneity) = 0.79). No significant between-study heterogeneity was found in all subjects under four genetic models (dominant model, recessive model, allele comparison and homozygosity comparison) for these three polymorphisms, respectively, so the fixed effects model was used to pool the result. Our result indicated that carriers of 49T might improve the risk of PCa in higher stages (Stages III-IV), carriers of long TA repeat might decrease the risk of PCa and 89L may not be an important risk factor for PCa. However, due to the limited sample sizes, this meta-analysis did not achieve sufficiently conclusive results. Still more well-designed studies should be performed to clarify the role of these three polymorphisms in the development of PCa.     

A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population

The effect of the polymorphism of the DNA repair gene ERCC2/XPD Asp312Asn on the risk of lung cancer was investigated in a northeastern Chinese population. A hospital-based case-control study consisted of 201 lung cancer cases and 171 cancer-free controls matched to age, sex, and ethnicity. A polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. Frequency of the variant C-allele of ERCC2 Asp312Asn was 0.006 among the controls in present study, which differs markedly from previous reports both in European ancestry populations and in other Chinese populations (all P < 0.001). The polymorphism was not associated with risk of lung cancer. Haplotype analysis including three previously studied polymorphisms (ERCC1 Asn118Asn, ERCC2 Arg156Arg, and ERCC2 Lys751Gln) revealed that a haplotype consisting of ERCC1Asn118Asn(G)-ERCC2 Arg156Arg(C)-ERCC2 Asp312Asn(G)-ERCC2 Lys751Gln(C) was marginally associated with an increased risk of lung cancer (OR = 3.61, 95% CI = 1.00-13.06, P = 0.04). Our data suggest that the polymorphism ERCC2 Lys751Gln or a haplotype encompassing the variant allele is associated with risk of lung cancer in this population. Studies including larger sample sizes are needed to elucidate the effects of these polymorphisms on lung cancer risk in this northeastern Chinese population.     

Calcitonin gene polymorphism CALCA-624 (T/C) and ovarian cancer

In a previous analysis, we reported an inverse association of dietary calcium intake with the risk of ovarian cancer (Goodman et al. 2002. Am J Epidemiol 156:148-57). The CALCA gene codes for calcitonin, an important regulator of bone calcium metabolism. Data from a population-based case-control study conducted in Hawaii were used to examine the hypothesis that a T --> C transition 624 base pairs upstream (-624) of the translation initiation codon of the CALCA gene influences the risk of ovarian malignancy. A structured interview was conducted for 182 histologically confirmed ovarian cancer cases and 219 controls. Blood specimens were collected from the subjects at their homes. A significant negative trend (P for trend: 0.02) in the odds ratios (ORs) was found with increasing intake of calcium. Women with any CALCA C allele were at nonsignificantly higher risk of ovarian cancer (OR: 1.5, 95% CI: 0.9-2.3) compared to women with the TT genotype and the risk increased with the number of C alleles (P for trend: 0.05). When further analyzed within ethnic subgroups, a significant positive association was found among Japanese for CALCA CT (OR: 2.3, 95% CI: 1.0-5.3) and CALCA CC (OR: 7.2, 95% CI: 1.1-46.0) compared with Japanese women who were homozygous for the T allele. The trend in risk associated with the C allele was most significant among women who had used oral contraceptives (P for trend: 0.05), had been pregnant (P for trend: 0.04), and had nonmucinous histological types of ovarian cancer (P for trend: 0.02). However, the association of ovarian cancer risk with the CALCA genotype was not significantly modified by any of the dietary, nondietary, or clinical variables included in this study. These preliminary data suggest a strong positive association of the CALCA C allele with the risk of ovarian cancer among some subgroups.     

Transforming Growth Factor β1-509C/T and +869T/C Polymorphisms on the Risk of Upper Digestive Tract Cancer: A Meta-Analysis Based on 10,917 Participants

The aim of this study was to assess the relationships between transforming growth factor β1-509C/T (rs1800469) and +869T/C (rs1800470) polymorphisms and the risk of upper digestive tract cancer (UDT cancer) by using a meta-analysis. We interrogated the databases of Medline, Embase and Wanfang (Chinese literature database) (latest update; December 15, 2011). Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were used to assess the strength of the associations. In total, 20 case-control studies were included in this meta-analysis. Overall, both TGF β1-509C/T and +869T/C polymorphisms were not associated with risk of UDT cancer [-509C/T: OR (95%CI) = 1.10 (0.99-1.22) for TT vs. C carries, P(heterogeneity) = 0.10; +869T/C: OR (95%CI) = 1.04 (0.88-1.23) for CC vs. T carriers, P(heterogeneity) = 0.02]. Subgroup analyses indicated that the -509T allele was associated with increased risk of UDT cancer in population-based studies (OR = 1.16 (1.04-1.31), P(heterogeneity) = 0.31 for TT vs. C carriers) and in small sample-sized studies (OR = 1.45 (1.15-1.84), P(heterogeneity) = 0.56 TT vs. C carriers). All subgroup analyses for the TGF β1+869T/C polymorphism indicated null association except for hepatocellular carcinoma. Interestingly, both the TGF β1-509T allele and the +869C allele were associated with decreased risk of hepatocellular cancer based on limited original studies. This meta-analysis indicated that TGF β1-509C/T rather than +869T/C is a potential risk factor for UDT cancer.     

Cytochrome P450 1A1 (<Emphasis Type="Italic">CYP1A1</Emphasis>) T3801C and A2455G polymorphisms in breast cancer risk: a meta-analysis

The cytochrome P450 1A1 gene (CYP1A1), encoding Phase I metabolic enzymes, appeared to be a candidate gene for breast cancer risk. However, studies on the association between polymorphisms in this gene and breast cancer have yielded conflicting results. We performed a meta-analysis to investigate the association with breast cancer of the CYP1A1 polymorphisms T3801C (9,316 cases and 12,714 controls) and A2455G (9,552 cases and 9,320 controls). In the genotype contrast of A2455G, both additive [GG vs AA, P = 0.04, fixed-effects OR 0.72; 95% CI (0.53–0.99), P = 0.95 for heterogeneity] and recessive [GG vs (GA + AA), P = 0.04, fixed-effects OR 0.73; 95% CI (0.53–0.99), P = 0.97 for heterogeneity] models produced significant results in east-Asians. In pre-menopausal women in a worldwide population, significant association between A2455G and breast cancer was also found using both models [additive model: P = 0.02, fixed-effects OR 0.52; 95% CI (0.29–0.92), P = 0.39 for heterogeneity; recessive model: P = 0.02, fixed-effects OR 0.51; 95% CI (0.29–0.90), P = 0.38 for heterogeneity]. Our meta-analysis suggests that an A2455G G/G genotype is associated with a trend of reduced breast cancer risk, both in east-Asian women and in pre-menopausal women worldwide, while the T3801C C allele might not be a risk factor for breast cancer. Larger scale primary studies are required to further evaluate the interaction of CYP1A1 polymorphisms and breast cancer risk in specific populations.     

Methylenetetrahydrofolate Reductase C677T polymorphism and breast cancer risk in Moroccan women

Background

Methylenetetrahydrofolate (MTHFR) enzyme plays an important role in folate metabolism which is involved in DNA methylation, repair, and synthesis.

Objective

We investigated if the MTHFR C677T polymorphism modulates the risk of developing breast cancer in Moroccan women.

Methods

Genotyping was performed by PCR-RFLP method on a sample of 96 patients with breast cancer and 117 controls.

Results

A positive correlation was found between the MTHFR C677T polymorphism and progesterone receptors expression (p= 0.04). According to menopausal status, the heterozygous CT (OR = 2.29 and P = 0.03) was statistically significant in pre-menopausal women. There was a significant association between C677T polymorphism and breast cancer risk in both additive (OR = 2.2, 95% CI = 1.24–3.86, p = 0.007) and dominant (OR = 2.10, CI 95% = 1.21–3.64, p = 0.008) models. In addition, the T allele were associated with a high breast cancer risk (OR = 1.59, 95% CI = 1.04–2.44, p = 0.03).

Conclusion

In the light of our preliminary study, 677T allele and 677CT MTHFR genotype may represent a genetic determinant increasing breast cancer risk in Moroccan women. A larger study including a larger sample size and more information is needed to confirm our conclusions.     

Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a meta-analysis

So far, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and lung cancer provide controversial or inconclusive results. To clarify the effect of MTHFR polymorphisms on the risk of lung cancer, a meta-analysis of all case-control observational studies was performed. The studies provided 5,111/6,415 cases/controls for C677T and 5,087/6,232 cases/controls for A1298C. The heterogeneity (P = 0.0001, I ² = 76.6%) for C677T among the eight studies was extreme. Cluster analyses based on the frequencies of the C677T genotype of the control group in each study revealed that the studies could not cluster together according to their ethnicity. The random effects (RE) model showed that the 677T allele was not associated with the risk of lung cancer compared with the C allele [OR = 1.12, 95% confidence interval (CI) (0.97–1.28), P = 0.12]. The contrast of homozygotes, recessive model, dominant model produced the same pattern of results as the allele contrast. In regard to the A1298C polymorphism, there was no heterogeneity among the seven studies comparing the C versus the A allele (P = 0.24, I ² = 24.4%), but no significant association was detected by the RE model or the fixed effects model [FE odds ratio (OR) = 0.99 (0.93–1.05) and RE OR = 1.00 (0.92–1.08)]. The effect of MTHFR polymorphisms (C677T, A1298C) on the risk of lung cancer was undetectable, even though analyzed on a relatively good number of subjects (totally 11,526 subjects) by meta-analysis (statistical power = 93.9%). Although MTHFR polymorphisms were associated with the risk of colorectal cancer, leukemia, and gastric cancer supported by other meta-analysis, our pooled data suggest no evidence for a major role of these two variants in carcinogenesis of lung cancer. The results implied that different tumors evolve by different pathological pathways and the roles of MTHFR in cancer is determined by its target genes.     

p73 G4C14-A4T14 polymorphism and cancer risk: a meta-analysis based on 27 case-control studies

p73 G4C14-A4T14 polymorphism has been hypothesised to be associated with the risk of cancer development by many epidemiological studies, however, the available results were conflicting. To derive a more precise estimation of association between the p73 G4C14-A4T14 polymorphism and risk of cancer, we performed a meta-analysis based on 8017 cancer cases and 11610 controls from 25 publications with 27 individual case-control studies. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. Overall, We found that the variant AT/AT homozygote was associated with a significantly increased risk of all types of cancer (homozygote comparison: OR = 1.35, 95% CI = 1.11-1.65; recessive model comparison: OR = 1.32, 95% CI = 1.11-1.58). In the subgroup analyses by ethnicity/country, the results suggested that AT/AT genotype was significantly associated with risk of cancer development among Caucasians and Asians, especially for the Americans and Japanese. Moreover, when stratifying by types of cancer, significantly increased cancer risks were observed for colorectal cancer, 'head and neck cancers' and 'other cancers'. Interestingly, when stratifying by source of controls, a significantly elevated risk was found among hospital-based studies but not among population-based studies. Limiting the analysis to the studies within Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study. This meta-analysis suggests that the p73 -AT allele may be a low-penetrant risk factor for cancer development.     

Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis

The methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been linked to the risk of developing breast cancer. A meta-analysis of 18 case-control studies investigating the association between the C677T and the A1298C polymorphisms of the MTHFR gene and breast cancer (BC) was carried out. The meta-analysis included genotype data on 5467/7336 and 3768/5276 cases/controls for C677T and A1298C, respectively. In the meta-analysis, the consistency of genetic effects across different ethnicities and the effect of menopausal status for various genetic contrasts were investigated. The overall analysis for investigating the association between the C677T allele T and the risk of developing BC showed significant heterogeneity (p = 0.08, I2 = 34%) and non-significant association [odds ratio (OR) 1.02; 95% confidence interval (0.95-1.10)]. The allele contrast was not significant in Caucasians (nine studies) and in East Asians (four studies) [OR 1.03 (0.93-1.14) and OR 0.96 (0.81-1.15), respectively] or in pre-menopausal (five studies) and post-menopausal (four studies) groups [OR 1.10 (0.94-1.29) and OR 1.06 (0.95-1.18), respectively]. The genotype contrast of the homozygotes (TT vs CC) produced significant results only for pre-menopausal cases [OR 1.46 (1.05-2.03)]. The recessive model for allele T produced significant association only in pre-menopausal cases [OR 1.49 (1.09-2.03)]. The dominant model for the effect of allele T produced no significant results, overall and in each subgroup. For the A1298C polymorphism, all genotype contrasts showed lack of association, overall and in Caucasians. In summary, the accumulated evidence supports an association in pre-menopausal women. BC is a complex disease with multifactorial etiology, and therefore, case-control studies that investigate gene-environment interaction might elucidate further the genetics of the disease.