We performed subgroup analyses by ethnicity (Asian or Caucasian), location of CRC (colon cancer or rectal cancer), study design (PB, HB, or FB), and type of CRC (sCRC or HNPCC). Using GG genotype as a reference, A carriers were associated with a significantly increased risk of CRC in both Asians (AA + AG vs GG: OR = 1.24, 95% CI = 1.04–1.49) and Caucasians (AA + AG vs GG: OR = 1.19, 95% CI = 1.01–1.40). This indicated that A carriers might be a low-penetrant risk factor for CRC in both Asian and Caucasian populations. When stratified by cancer location, significant associations between A carriers and CRC risk were found in both subsets of patients with colon cancer (AA + AG vs GG: OR = 1.20, 95% CI = 1.05–1.38) and rectal cancer (AA + AG vs GG: OR = 1.39, 95% CI = 1.20–1.62). Subgroup analysis by study design indicated that significant association between the CCND1 G870A polymorphism and the risk of CRC was only observed in HB studies (AA + AG vs GG: OR = 1.30, 95% CI = 1.14–1.47), rather than PB (OR = 1.16, 95% CI = 1.00–1.35) or FB studies (OR = 0.92, 95% CI = 0.38–2.23). According to analysis by cancer type, no significant association was noted between the CCND1 G870A polymorphism and an increased risk of CRC in patients with sCRC (AA + AG vs GG: OR = 1.24, 95% CI = 0.96–1.60) and HNPCC (AA + AG vs GG: OR = 0.93, 95% CI = 0.64–1.36), but a significantly increased CRC risk was found in sCRC patients with genotype AG (AG vs GG: OR = 1.30, 95% CI = 1.11–1.53) (Fig. 3, Table 3).
We performed a sensitivity analysis through sequentially excluded individual studies. No individual study affected the overall OR dominantly, statistically similar results were obtained, suggesting the stability of this meta-analysis (data not shown). We used the Begg funnel plot and the Egger test. The shape of the funnel plots of the 27 publications appeared symmetrical for the AA + AG versus GG model (Fig. 4), indicating no evidence of significant publication bias in this meta-analysis. And the Egger test results also supported that there was no evidence of publication bias (P > .05).
As we know, CCND1 has been considered to be a cancer gene which could regulate progression from the G1 phase of the cell cycle to the S phase. Cells with the mutant allele accumulate mutations as a result of defective mismatch repair and bypass the G1-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. Variant polymorphisms can result in abnormal protein levels and lead to cancer. The CCND1 over expression has been reported to occur in 72% of colorectal tumors. However, results of case-control studies about this genetic polymorphism were inconsistent. A few meta-analyses[24–27] were also designed to confirm the influence of CCND1 G870A polymorphism on CRC susceptibility. These analyses found that A carriers of the CCND1 G870A polymorphism were significantly associated with an increased risk of CRC. However, their detailed descriptions on ethnicity, cancer location, study design, and family history varied significantly. Zou et al, the most recent study published in 2012 included 23 case-control studies, and concluded that the CCND1 870A allele might be a low-penetrant risk factor for CRC. The result was consistent with the findings reported by Yang et al and Zhang et al. But in further stratified analyses by ethnicity and study design, such a correlation was not found in any subsets of participants. This result was contradictory to those from the other 3 meta-analyses,[24,25,27] which observed an increased risk in the subgroups of sCRC and in Caucasians.
It has been shown in prior studies that CCND1 870A allele carriers had been confirmed that may be an increase the risk of developing esophageal cancer and hepatocellular carcinoma.[64,65] In this study, we come to a similar conclusion that the CCND1 G870A polymorphism is a potential factor of CRC. However, a few meta-analyses[66,67] reported that the CCND1 G870A polymorphism may not be associated with an increased risk factor for cervical cancer and head and neck cancer. Perhaps this is due to similar CCND1 gene expressions in gastrointestinal carcinomas rather than tumors of other systems.
Compared with previous meta-analyses, we found a significant association between the CCND1 G870A polymorphism and the CRC risk in many different subgroups. We inferred that 3 reasons might explain the different results between our study and prior studies. First, a larger number of case-control studies were included in our meta-analysis than previous studies, so our conclusion seemed to be more powerful and reliable. Second, no conspicuous publication bias was detected in our study, which indicated that the entire pooled results might be unbiased. Third, comparisons of all genetic models were performed in our study, suggesting that this polymorphism analysis might be more comprehensive and credible.
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