Recently, there have been a number of studies on the association between cyclin D1 G870A polymorphism and nasopharyngeal carcinoma risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between cyclin D1 G870A polymorphism and the risk of nasopharyngeal carcinoma. No significant association was found between cyclin D1 G870A polymorphism and nasopharyngeal carcinoma risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Caucasian subgroup, and no significant association in any genetic models among Asians was observed. In summary, positive results have been shown on the search for polymorphic variants influencing the risk of NPC. This meta-analysis provides evidence of the association between CCND1 G870A polymorphism and NPC risk, supporting the hypothesis that CCND1 870A allele probably acts as an important NPC protective factor in Caucasians but not in Asians. Since the results of our meta-analysis are preliminary and may be biased by the relatively small number of subjects, they still need to be validated by well-designed studies using larger samples in the future.
Nasopharyngeal carcinoma (NPC) is a malignant epithelial cancer with a strikingly geographic and ethnic distribution. The incidence of NPC is higher in Southeast Asia and Africa, but lower among Caucasians in North America and Europe. Epidemiological studies and experimental researches have implicated genetic susceptibility, Epstein-Barr viral (EBV) infection, and environmental factors in the specific and multifactorial etiology of NPC [
Cyclin D1, encoded by
Considering a single study may be insufficient to identify the effect of CCND1 G870A polymorphism on NPC, and the published results have been controversial. We therefore performed a meta-analysis to assess the association between CCND1 G870A polymorphism and NPC susceptibility.
We searched the literature databases including PubMed, ISI Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Google Scholar (up to November 08, 2012). The search strategy for identifying all possible studies involved usage of the following keywords: “cyclin D1 or CCND1” and “polymorphism or variant or genotype or SNP” and “nasopharyngeal carcinoma or nasopharyngeal cancer or squamous cell cancer of the head and neck or head and neck cancer”. All related studies without language limitation were included. The reference lists of the additional articles reporting the association between CCND1 G870A polymorphism and NPC were hand searched.
All the studies included in the meta-analysis met the following inclusion criteria: (1) original papers associated cyclin D1 G870A polymorphism with NPC; (2) case control or cohort design was used, and (3) genotype distribution information, odds ratio (OR) with its 95% confidence interval (CIs), and
Data extraction for compliance with the inclusion/exclusion criteria was performed independently by two reviewers. Disagreements were resolved by further discussion among all authors. For each included study, the following information was extracted according to a fixed protocol: (1) name of the first author; (2) year of publication; (3) country; (4) ethnicity; (5) genotyping method; (6) genotype distribution in cases and controls; (7)
The association between cyclin D1 G870A polymorphism and NPC was estimated by calculating pooled odds ratio (OR) and 95% confidence interval (CI) under a homozygote comparison model (AA versus GG), a heterozygote comparison model (GA versus GG), and a dominant model (AA + GA versus GG), respectively. The significance of pooled OR was determined by
As shown in Figure
Flow chart of study selection based on the inclusion and exclusion criteria.
Characteristics of the studies included in this meta-analysis were presented in Table
Characteristics of the studies included in the meta-analysis.
First author | Year | Country | Ethnicity | Genotyping method | Genotype distribution |
|
References | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Case | Control | |||||||||||
GG | GA | AA | GG | GA | AA | |||||||
Catarino | 2008 | Portugal | European | PCR-RFLP | 23 | 40 | 21 | 40 | 138 | 69 | 0.036 | [ |
Catarino | 2006 | Portugal | European | PCR-RFLP | 26 | 42 | 26 | 28 | 105 | 54 | 0.047 | [ |
Deng | 2002 | China (mainland) | Asian | DHPLC | 19 | 48 | 17 | 14 | 42 | 35 | 0.811 | [ |
Shih | 2012 | China (Taiwan) | Asian | PCR-RFLP | 23 | 86 | 67 | 28 | 105 | 43 | 0.007 | [ |
Sui | 2009 | China (mainland) | Asian | PCR-RFLP | 60 | 110 | 71 | 115 | 124 | 33 | 0.962 | [ |
The results on the association between cyclin D1 G870A polymorphism and NPC risk and the heterogeneity test were shown in Table
Meta-analysis of the association between cyclin D1 G807A polymorphism and nasopharyngeal cancer risk.
Comparisons | Odds ratio | 95% confidence interval |
|
Heterogeneity | Effects model | |
---|---|---|---|---|---|---|
|
|
|||||
A versus G | 1.010 | 0.628–1.622 | 0.969 | 90.5% | 0.000 | Random |
Asians | 1.221 | 0.647–2.304 | 0.538 | 91.7% | 0.000 | |
Caucasians | 0.754 | 0.589–0.967 | 0.026 | 0.0% | 0.989 | |
AA versus GG | 0.976 | 0.368–2.592 | 0.961 | 90.2% | 0.000 | Random |
Asians | 1.475 | 0.407–5.345 | 0.554 | 90.7% | 0.000 | |
Caucasians | 0.524 | 0.317–0.865 | 0.011 | 0.0% | 0.968 | |
GA versus GG | 0.811 | 0.460–1.429 | 0.469 | 77.6% | 0.001 | Random |
Asians | 1.236 | 0.791–1.913 | 0.353 | 42.6% | 0.175 | |
Caucasians | 0.467 | 0.299–0.730 | 0.001 | 0.0% | 0.730 | |
GA + AA versus GG | 0.856 | 0.430–1.707 | 0.660 | 86.6% | 0.000 | Random |
Asians | 1.277 | 0.631–2.584 | 0.497 | 78.4% | 0.010 | |
Caucasians | 0.487 | 0.319–0.741 | 0.001 | 0.0% | 0.804 |
Forest plots of cyclin D1 G870A polymorphism in nasopharyngeal carcinoma versus normal control and subgroup analyses for A genotype compared with G genotype. The squares and horizontal lines correspond to the study specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI. OR: odds ratio.
Forest plots of cyclin D1 G870A polymorphism in nasopharyngeal carcinoma versus normal control and subgroup analyses for AA genotype compared with GG genotype.
Forest plots of cyclin D1 G870A polymorphism in nasopharyngeal carcinoma versus normal control and subgroup analyses for GA genotype compared with GG genotype.
Forest plots of cyclin D1 G870A polymorphism in nasopharyngeal carcinoma versus normal control and subgroup analyses for AA + GA genotype compared with GG genotype.
Statistically significant heterogeneity was observed in trials using the following analyses with Q statistic tests (A versus G:
Egger’s test and Beggar’s test were performed to assess publication bias. Analysis using the Egger weighted regression method did not indicate publication bias for two of the four genetic models (heterozygote comparison model GA versus GG:
Publication bias test for cyclin D1 G807A polymorphism.
Comparisons | Egger’s test | Beggar’s test |
||
---|---|---|---|---|
Coefficient |
|
95% CI | ||
A versus G | −15.91 | 0.007 | −23.44–−8.39 | 0.086 |
AA versus GG | −14.52 | 0.037 | −27.36–−1.68 | 0.027 |
GA versus GG | −6.03 | 0.143 | −15.77–3.71 | 0.221 |
GA + AA versus GG | −8.39 | 0.082 | −18.76–1.96 | 0.462 |
Cell cycle regulation plays an important role in the development of cancer by influencing cell proliferation, differentiation, and apoptosis [
Deng et al. found that cyclin D1 G870A polymorphism was associated with the susceptibility to NPC, because the GG and AG genotypes in NPC patients were significantly higher than those in normal controls [
In the subgroup meta-analysis based on ethnicity, compared with G allele, a significantly decreased risk of NPC was associated with A allele; compared with GG genotype, a significantly decreased risk of NPC was associated with AA genotype, GA genotype, and combined AA/GA genotype in the Caucasian subgroup. Further investigations on a larger scale on Caucasian population may be needed to confirm this result. In the Asian subgroup, no significant association was found in the different genetic models. Our results indicate that ethnicity may be a critical factor affecting effects of the polymorphic alleles on susceptibility to NPC.
Despite these advantages, some limitations in the current meta-analysis should be considered with caution. Firstly, the controls were not uniformly defined. Although most control groups were selected from healthy populations, some might have a benign disease. Therefore, there is a lack of proper matching, and the results are based on unadjusted estimates. Secondly, the analysis did not consider gene-gene and gene-environment interactions due to the lack of sufficient data. Thirdly, environmental and lifestyle-related factors may influence the results of this analysis. A more precise analysis with individual data available might be considered, which could allow an adjustment estimate by sex, age, body weight, and lifestyle such as smoking and alcohol drinking. Fourthly, there is evidence of publication bias in the formal evaluation used in this study. The results of our meta-analysis may be biased by the relatively small number of subjects. Therefore, our conclusion still needs to be validated by well-designed studies with larger sample size in the future. Finally, and most importantly, whether the CCND1 G870A polymorphism is independently predictive of cancer risk remains controversial.
In summary, positive results have been shown in the search for polymorphic variants influencing the risk of NPC. This meta-analysis provides evidence of the association between CCND1 G870A polymorphism and NPC risk, supporting the hypothesis that CCND1 870A allele probably acts as an important NPC protective factor in Caucasians, but not in Asians.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by grants from the National Science Foundation of China (Grant no. 81101491), Natural Science Foundation of Zhejiang Province of China (Grant no. Y2110843), and Zhejiang medical and health science and technology program (Grant no. 2012KYB153).