Comprehensive Review of Genetic Association Studies and Meta-Analyses on miRNA Polymorphisms and Cancer Risk

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444) and cancer risk by using a two-sided meta-analytic approach.

Methods

An updated meta-analysis based on 53 independent case-control studies consisting of 27573 cancer cases and 34791 controls was performed. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association.

Results

Overall, the pooled analysis showed that mir-196a2 rs11614913 was associated with a decreased cancer risk (OR = 0.846, P = 0.004, TT vs. CC) while other miRNA SNPs showed no association with overall cancer risk. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between miR-146a rs2910164 and overall cancer risk in Caucasian population under recessive model (OR = 1.274, 95%CI = 1.096–1.481, P = 0.002). Stratified analysis by cancer type also associated mir-196a2 rs11614913 with lung and colorectal cancer at allelic and genotypic level.

Conclusions

The present meta-analysis suggests an important role of mir-196a2 rs11614913 polymorphism with overall cancer risk especially in Asian population. Further studies with large sample size are needed to evaluate and confirm this association.     

Effects of Common Polymorphism rs11614913 in Hsa-miR-196a2 on Lung Cancer Risk

Background

Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the pathogenesis of lung cancer by altering the expression of tumor-related microRNAs. Several studies were investigated in recent years to evaluate the association between hsa-miR-196a2 rs11614913 polymorphism and increased/decreased lung cancer risk. In the present study, we performed a meta-analysis to systematically summarize the possible association.

Methodology/Principal Findings

We performed a meta-analysis of 4 case-control studies that included 2219 lung-cancer cases and 2232 cancer-free controls. We evaluated the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In the overall analysis, it was found that the rs11614913 polymorphism significantly elevated the risk of lung cancer (CC versus (vs.) TT OR = 1.26, 95% CI 1.07–1.49, P = 0.007; CC/CT vs. TT: OR = 1.13, 95% CI 0.98–1.29, P = 0.007; C vs. T: OR = 1.12, 95% CI 1.03–1.22, P = 0.008). In the subgroup analysis by ethnicity, statistically significantly increased cancer risk was found among Asians (CC vs. TT: OR = 1.30, 95% CI 1.10–1.54, P = 0.003; CT vs. TT: OR = 1.16, 95% CI 1.01–1.34, P = 0.039; CC vs. CT/TT: OR = 1.21, 95% CI 1.04–1.41, P = 0.012; C vs. T: OR = 1.14, 95% CI 1.05–1.25, P = 0.002). For Europeans, a significant association with lung cancer risk was found in recessive model (CC vs. CT/TT: OR = 0.63, 95% CI 0.40–0.98, P = 0.040). No publication bias was found in this study.

Conclusions/Significance

Our meta-analysis suggests that the rs11614913 polymorphism is significant associated with the increased risk of lung cancer, especially in Asians. Besides, the C allele of rs11614913 polymorphism may contribute to increased lung cancer risk.     

Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk

Background

Genetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis.

Methods

Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses.

Results

rs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16–3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20–2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14–2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05–2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15–0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk.

Conclusions

rs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.     

Hsa-miR-196a2 Rs11614913 polymorphism contributes to cancer susceptibility: evidence from 15 case-control studies

Background

MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results.

Methodology/Principal Findings

We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR = 1.18, 95% CI = 1.03–1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR = 1.11, 95%CI = 1.01–1.23, P _{heterogeneity} = 0.210) and lung cancer risk (OR = 1.25, 95%CI = 1.06–1.46, P _{heterogeneity} = 0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR = 1.24, 95% CI = 1.07–1.43, P _{heterogeneity} = 0.006).

Conclusions

These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers.     

Association Studies of ERCC1 Polymorphisms with Lung Cancer Susceptibility: A Systematic Review and Meta-Analysis

Background

Excision repair cross-complimentary group 1 (ERCC1) is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial.

Objectives

An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C), rs3212986 (C>A), rs3212961 (A>C), rs3212948 (G>C), rs2298881 (C>A).

Methods

Several major databases (MEDLINE, EMBASE and Scopus) and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations.

Results

Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls) suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04–1.48, P = 0.02). However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67–0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69–0.91, P = 0.001).

Conclusion

Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are needed to validate these findings.     

Replication Study in Chinese Population and Meta-Analysis Supports Association of the 5p15.33 Locus with Lung Cancer

Background

Common genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L), have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS); however, subsequent replication studies yielded controversial results.

Methodology and Findings

A hospital-based case-control study in a Chinese population was conducted to replicate the association, and then a meta-analysis combining our non-overlapping new data and previously published data was performed to clearly discern the real effect of lung cancer susceptibility. In our study with 611 cases and 1062 controls, the minor allele T carrier (TT plus CT) group conferred an OR of 0.801 (95% CI = 0.654–0.981) under the dominant model. The meta-analysis comprising 9111 cases and 11424 controls further confirmed the significant association in the dominant model (OR = 0.842, 95% CI = 0.795–0.891). By stratified analysis, we revealed that ethnicity and study design might constitute the source of between-study heterogeneity. Besides, the sensitivity and cumulative analyses indicated the high stability of the results.

Conclusion

The results from our case-control study and meta-analysis provide convincing evidence that rs401681 is significantly associated with lung cancer risk.     

The SNP rs402710 in 5p15.33 Is Associated with Lung Cancer Risk: A Replication Study in Chinese Population and a Meta-Analysis

Background

Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in the world. A single nucleotide polymorphism (SNP), rs402710, located in 5p15.33, was firstly identified to be associated with the lung cancer risk in a genome-wide association study. However, some following replication studies yielded inconsistent results.

Methodology and Findings

A case-control study of 611 cases and 1062 controls in a Chinese population was conducted, and then a meta-analysis integrating the current and previously published studies with a total 31811 cases and 36333 controls was performed to explore the real effect of rs402710 on lung cancer susceptibility. Significant associations between the SNP rs402710 and lung cancer risk were observed in both case-control study and meta-analysis, with ORs equal to 0.77 (95%CI = 0.63–0.95) and 0.83 (95%CI = 0.81–0.86) in dominant model, respectively. By stratified analysis of our case-control study, the associations were also observed in never smoker group and non-small cell lung cancer(NSCLC) group with ORs equal to 0.71 (95%CI = 0.53–0.95) and 0.69 (95%CI = 0.55–0.87), which was remarkable that larger effect of the minor allele T was seen in the two groups than that in overall lung cancer. Besides, the sensitive and cumulative analysis indicated the robust stability of the current results of meta-analysis.

Conclusion

The results from our replication study and the meta-analysis provided firm evidence that rs402710 T allele significantly contributed to decreased lung cancer risk, and the case-control study implied that the variant may yield stronger effect on NSCLC and never smokers. However, the mechanism underlying the polymorphism conferring susceptibility to lung cancer is warranted to clarify in the follow-up studies.     

Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma

Background

The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods

In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI).

Results

We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011).

Conclusions

Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.     

Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis

Backgrounds

The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 −196 to −174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies.

Methodology/Principle Findings

A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 −196 to −174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04–2.60 for TLR2 −196 to −174 del; OR = 1.19, 95% CI: 1.01–1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120–1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 −196 to −174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13–2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16–1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 −196 to −174 del and TLR4 rs4986791.

Conclusions/Significance

This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.     

Genetic Variant rs7758229 in 6q26–q27 Is Not Associated with Colorectal Cancer Risk in a Chinese Population

Background

A recent genome-wide association study has identified a new genetic variant rs7758229 in SLC22A3 for colorectal cancer susceptibility in a Japanese population, but it is unknown whether this newly identified variant is associated with colorectal cancer in other populations, including the Chinese population.

Methods

We examined the associations between rs7758229 and colorectal cancer risk among 1,147 cases and 1,203 controls matched by age and sex. Logistic regression model was used to assess the associations.

Results

No significant association was found between rs7758229 and colorectal cancer risk (OR = 0.95, 95%CI  = 0.84–1.09, P = 0.463). Similar results were observed in the stratification of tumor location (OR  = 0.94, 95%CI = 0.80–1.11, P = 0.481 for colon cancer, and OR  = 0.96, 95%CI  = 0.82–1.13, P = 0.621 for rectum cancer).

Conclusions

Our findings did not support an association between rs7758229 in 6q26-q27 and the risk of colorectal cancer in a Chinese population.     

Interaction between Polymorphisms in Pre-MiRNA Genes and Cooking Oil Fume Exposure on the Risk of Lung Cancer in Chinese Non-Smoking Female Population

Background

Both genetic polymorphisms and environmental risk factors play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of interaction between polymorphisms in pre-miRNA genes and cooking oil fume exposure on the risk of lung cancer.

Methods

A hospital-based case-control study of 258 cases and 310 controls was conducted. Six polymorphisms in miRNAs were determined by Taqman allelic discrimination method. The gene-environment interactions were assessed on both additive and multiplicative scale. The statistical analyses were performed mostly with SPSS.

Results

The combination of the risk genotypes of five miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-608 rs4919510, miR-27a rs895819 and miR-423 rs6505162) with risk factor (cooking oil fume exposure) contributed to a significantly higher risk of lung cancer, and the corresponding ORs (95% confidence intervals) were 1.91(1.04-3.52), 1.94 (1.16-3.25), 2.06 (1.22-3.49), 1.76 (1.03-2.98) and 2.13 (1.29-3.51). The individuals with both risk genotypes of miRNA SNPs and exposure to risk factor (cooking oil fumes) were in a higher risk of lung cancer than persons with only one of the two risk factors (ORs were 1.91, 1.05 and 1.41 for miR-146a rs2910164, ORs were 1.94, 1.23 and 1.34 for miR-196a2 rs11614913, ORs were 2.06, 1.41 and 1.68 for miR-608 rs4919510, ORs were 1.76, 0.82 and 1.07 for miR-27a rs895819, and ORs were 2.13, 1.15 and 1.02 for miR-423 rs6505162, respectively). All the measures of biological interaction indicate that there were not indeed biological interactions between the six SNPs of miRNAs and exposure to cooking oil fumes on an additive scale. Logistic models suggested that the gene-environment interactions were not statistically significant on a multiplicative scale.

Conclusions

The interactions between miRNA SNPs and cooking oil fume exposure suggested by ORs of different combination were not statistically significant.     

Quantitative Assessment of the Influence of TP63 Gene Polymorphisms and Lung Cancer Risk: Evidence Based on 93,751 Subjects

Background

Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results.

Methods

PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.

Results

A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14–1.25; P<10⁻⁵) and 1.19 (95% CI: 1.13–1.25; P<10⁻⁵) was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians (per-allele OR = 1.22, 95% CI: 1.17–1.27; P<10⁻⁵); whereas no significant associations were found among Caucasians for rs10937405. In the sub-group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma.

Conclusions

Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk-conferring factors for the development of lung cancer, especially for East Asian populations.     

Association of SMAD7 rs12953717 Polymorphism with Cancer: A Meta-Analysis

Background

Accumulating evidence has suggested that Mothers against decapentaplegic homolog 7 (SMAD7) rs12953717 polymorphism might be related to cancer risk. However, epidemiologic findings have been inconsistent. We therefore performed a meta-analysis to clarify the association between the SMAD7 rs12953717 polymorphism and cancer risk.

Methods

A comprehensive search was conducted to identify all eligible studies of SMAD7 rs12953717 polymorphism and cancer risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. Heterogeneity, publication bias, and sensitivity analysis were also explored.

Results

A total of 14 case-control studies, including 16928 cases and 14781 controls, were included in the present meta-analysis. The overall results showed that the variant genotypes were associated with a significantly increased risk of all cancer types (homozygote comparison, OR = 1.23, 95%CI = 1.10–1.38, P<0.01; heterozygote comparison, OR = 1.12, 95%CI = 1.02–1.22, P = 0.02; recessive model, OR = 1.17, 95%CI = 1.07–1.29, P<0.01; dominant model, OR = 1.15, 95%CI = 1.06–1.25, P<0.01; allelic model, OR = 1.12, 95%CI = 1.06–1.18, P<0.01). Further sensitivity analysis confirmed the significant association. In the subgroup analysis by ethnicity, SMAD7 rs12953717 polymorphism was significantly associated with cancer risk in both Caucasians and Asians. In the subgroup analysis by cancer types, SMAD7 rs12953717 polymorphism was significantly associated with colorectal cancer.

Conclusions

Our investigations demonstrate that rs12953717 polymorphism is associated with the susceptibility of cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

Lack of Association between NADPH Quinone Oxidoreductase 1 (NQO1) Gene C609T Polymorphism and Lung Cancer: A Case-Control Study and a Meta-Analysis

Background

The association between NAD(P)H:quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and lung cancer has been widely evaluated, and a definitive answer so far is lacking. We first conducted a case-control study to assess this association in northeastern Han Chinese, and then performed a meta-analysis to further address this issue.

Methodology/Principal Findings

This case-control study involved 684 patients clinically diagnosed as lung cancer and 602 age-matched cancer-free controls from Harbin city, Heilongjiang province, China. Genotyping was conducted using the PCR-LDR (ligase detection reactions) method. Meta-analysis was managed by STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between lung cancer patients and controls, consistent with the results of the further meta-analysis involving 7286 patients and 9167 controls under both allelic (odds ratio (OR) = 0.99; 95% confidence interval (CI): 0.92–1.06; P = 0.692) and dominant (OR = 0.98; 95% CI: 0.89–1.08; P = 0.637) models. However, there was moderate evidence of between-study heterogeneity and low probability of publication bias. Further subgroup analyses by ethnicity, source of controls and sample size detected no positive associations in this meta-analysis.

Conclusions

Our study in northeastern Han Chinese, along with the meta-analysis, failed to confirm the association of NQO1 gene C609T polymorphism with lung cancer risk, even across different ethnic populations.     

A Common Polymorphism near the ESR1 Gene Is Associated with Risk of Breast Cancer: Evidence from a Case-Control Study and a Meta-Analysis

Background

Genome-wide association studies have reported that a polymorphism near the estrogen receptor gene (ESR1) (rs2046210) is associated with a risk of breast cancer, with the A allele conferring an increased risk. However, considering the controversial results from more recent replicated studies, we conducted a case-control study in an independent Chinese Han population and a meta-analysis to clarify the association of this polymorphism with breast cancer risk.

Method and Findings

A hospital-based case-control study including 461 cases and 537 controls from a Chinese Han population was conducted initially, and this study showed that the rs2046210 A allele was significantly associated with breast cancer risk, with an OR of 1.32 (95% CI  = 1.10–1.59). Subsequently, a meta-analysis integrating the current study and previous publications with a total of 53,379 cases and 55,493 controls was performed to further confirm our findings. Similarly, a significant association between this polymorphism and breast cancer risk was also observed in the overall population especially among Asians, with ORs for per A allele of 1.14 (95% CI  = 1.10–1.18) in the overall population and 1.27 (95% CI  = 1.23–1.31) in the Asian population.

Conclusion

Our results provide strong evidence to support that the common polymorphism near the ESR1 gene, rs2046210, is associated with an increased risk of breast cancer in Asian and European populations but not in Africans, although the biological mechanisms need to be further investigated.     

Single Nucleotide Polymorphism in ATM Gene,Cooking Oil Fumes and Lung Adenocarcinoma Susceptibility in Chinese Female Non-Smokers: A Case-Control Study

Background

The ataxia-telangiectasia mutated (ATM) gene plays an important role in the DNA double-strand breaks repair pathway. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ATM -111G>A (rs189037) polymorphism, environmental risk factors and the risk of lung adenocarcinoma in Chinese female non-smokers.

Methods

A hospital-based case-control study of 487 lung cancer patients and 516 matched cancer-free controls was conducted. Information concerning demographic and environmental risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, 10 ml venous blood was collected from each subject for biomarker testing. Single nucleotide polymorphism was determined by using TaqMan method.

Results

This study showed that the individuals with ATM rs189037 AA genotype were at an increased risk for lung adenocarcinoma compared with those carrying the GA or GG genotype (adjusted odds ratios (OR) 1.44, 95% confidence interval (CI) 1.02–2.02, P = 0.039). The stratified analysis suggested that increased risk associated with ATM rs189037 AA genotype in individuals who never or seldom were exposed to cooking oil fumes (adjusted OR 1.89, 95%CI 1.03–3.49, P = 0.040).

Conclusions

ATM rs189037 might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, ATM rs189037 AA genotype might be a risk factor of lung adenocarcinoma among female non-smokers without cooking oil fume exposure.     

The Functional Significance of MicroRNA-29c in Patients with Colorectal Cancer: A Potential Circulating Biomarker for Predicting Early Relapse

Background

The recurrence of colorectal cancer (CRC) is frequent within the first year of curative resection surgery and may be unavoidable. microRNAs have been suggested to play roles in carcinogenesis and cancer recurrence. We recently identified microRNA-29c (miRNA-29c) as a predictor of early recurrence in CRC. In the present study, we further investigated the functions and serum level of miRNA-29c in relation to early recurrence of CRC.

Methods

First we further confirmed overexpression of miRNA-29c in non-early relapse subjects. Gain-of-function in vitro studies were used to evaluate the effect of miRNA-29c on cell proliferation, migration, invasion, and cell cycle progression. The colon cancer cell line Caco2 and a stable clone overexpressing miRNA-29c were xenografted to evaluate the in vivo effect of miRNA-29c in null mice. Finally, circulating miRNA-29c was investigated as a potential biomarker for identifying early relapse.

Results

miRNA-29c expression significantly decreased during early relapse compared to non-early relapse in UICC stage II and III CRC patients (P = 0.021). In vitro studies showed that overexpression of miRNA-29c inhibited cell proliferation and migration. The cell cycle studies also revealed that miRNA-29c caused an accumulation of the G1 and G2 population. In vivo, miRNA-29c suppressed tumor growth in null mice. The serum miRNA-29c increased significantly in early relapsed patients compared to non-early elapsed patients (P = 0.012).

Conclusions

miRNA-29c shows anti-tumorigenesis activity, and preoperative circulating miRNA-29c levels can be used to predict postoperative early relapse of CRC.     

Contributory Role of Five Common Polymorphisms of RAGE and APE1 Genes in Lung Cancer among Han Chinese

Background

Lung cancer is the leading cause of cancer mortality in China. Given the ubiquitous nature of gene-to-gene interaction in lung carcinogenesis, we sought to evaluate five common polymorphisms from advanced glycosylation end product-specific receptor (RAGE) and apurinic/apyrimidinic endonuclease 1 (APE1) genes in association with lung cancer among Han Chinese.

Methods and Results

819 patients with lung cancer and 803 cancer-free controls were recruited from Qiqihar city. Genotypes of five examined polymorphisms (RAGE gene: rs1800625, rs1800624, rs2070600; APE1 gene: rs1760944, rs1130409) were determined by ligase detection reaction method. Data were analyzed by R software and multifactor dimensionality reduction (MDR). Hardy-Weinberg equilibrium was satisfied for all five polymorphisms. Overall differences in the genotype and allele distributions were significant for rs1800625 (P_genotype<0.0005; P_allele<0.0005), rs2070600 (P_genotype = 0.005; P_allele = 0.004) and rs1130409 (P_genotype = 0.009; P_allele = 0.004) polymorphisms. Haplotype C-A-A (alleles in order of rs1800625, rs1800624 and rs2070600) of RAGE gene was overrepresented in patients, and conferred a 2.1-fold increased risk of lung cancer (95% confidence interval: 1.52–2.91), independent of confounding factors. Further application of MDR method to five examined polymorphisms identified the overall best interaction model including rs2070600 and rs1130409 polymorphisms. This model had a maximal testing accuracy of 64.63% and a maximal cross-validation consistency of 9 out of 10 at the significant level of 0.006.

Conclusions

Our findings demonstrated a potential interactive contribution of RAGE and APE1 genes to the pathogenesis of lung cancer among Han Chinese. Further studies are warranted to confirm or refute these findings.