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. 2016 Apr 4;4(6):1078–1084. doi: 10.3892/mco.2016.844

CCND1 G870A polymorphism and colorectal cancer risk: An updated meta-analysis

XIAO-MING XU 1,2,*, XIAO-BING NI 1,2,*, GONG-LI YANG 2, ZHI-GUO LUO 3, YU-MING NIU 1,2,✉, MING SHEN 4,✉
PMCID: PMC4887936  PMID: 27284448

Abstract

Molecular epidemiological studies have revealed a closer association between cyclin D1 (CCND1) polymorphism and the risk of colorectal cancer; however, the results were inconsistent. The aim of the present meta-analysis was to investigate the association between CCND1 G870A polymorphism and colorectal cancer risk. Online electronic databases (PubMed and Embase) were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between CCND1 G870A polymorphism and the risk of colorectal cancer. In addition, heterogeneity, publication bias and sensitivity analysis were performed to guarantee the statistical power. In total, 23 published case-control studies with 6,320 patients and 8,252 controls were selected. Significantly increased risks were observed in four genetic models (A vs. G: OR=1.09, 95% CI=1.00–1.18, I2=54.3%; GA vs. GG: OR=1.13, 95% CI=1.04–1.24, I2=18.2%; AA vs. GG, OR=1.17: 95% CI=1.00–1.38, I2=52.5%; GA+AA vs. GG: OR=1.14, 95% CI=1.05–1.24, I2=33.8%). Similarly, significant associations were also identified in the stratified analysis in the cancer subtype of sporadic colorectal cancer (GA vs. GG: OR=1.21, 95% CI=1.04–1.42, I2=24.1%; GA+AA vs. GG: OR=1.18, 95% CI=1.02–1.37, I2=35.0%), Caucasian population (GA vs. GG, OR=1.14, 95% CI=1.02–1.28, I2=19.8%; GA+AA vs. GG, OR=1.14, 95% CI=1.02–1.27, I2=37.5%) and other subgroups of control design and genotyping type. The present updated meta-analysis suggested that CCND1 G870A may present an increased risk for developing colorectal cancer, particularly in sporadic colorectal cancer and a Caucasian population.

Keywords: cyclin D1, polymorphism, colorectal cancer

Introduction

Colorectal cancer is one of the most common malignant diseases. In 2009, there were 146,970 new patients and 49,920 mortalities in the United States, with colorectal cancer ranking third overall in terms of incidence and mortality in men and women (1). Colorectal cancer is a multifactorial disease, resulting from complex interactions between environmental factors and genetic mutations. A number of studies have revealed that diet may be involved in the development of colorectal cancer (2,3). The abnormal intake of animal meat, fat, vegetables and vitamins may increase the risk of development of colorectal cancer. In addition, family history and genetic factors are also closely associated with colorectal cancer; for example, MutS homolog 2 (MSH2) and MutL homolog 1 (MLH1) gene mutations are associated with hereditary non-polyposis colorectal cancer (3).

Aberrant cellular proliferation is closely associated with the development of cancers. The cyclin family is considered to exert a key role in cell proliferation. Cyclin D1 (CCND1) is a major regulator protein, which fulfills a critical role during transition from the growth (G)1 to the synthesis (S) phase, promoting the progression of the cell cycle during cell mitosis by adhering to cyclin-dependent kinases (CDKs) 4 and 6 (4,5). The constitutively increased expression of CCND1 is observed in numerous malignant cancers, and is associated with a poor prognosis (6–8).

Single nucleotide polymorphisms (SNPs) are able to change the structure of the genome and influence protein expression and function, which leads to abnormal cell proliferation and an increased risk of cancer (9). The most common mutation locus of the CCND1 gene is at codon 242, with a nucleotide change from guanine (G) to adenine (A) in exon 4. The A allele increases the frequency of alternative splicing during cell transcription, leading to an elevated level of CCND1, and consequently resulting in abnormal cell proliferation and an escape from apoptosis (10).

In 2009, Kong et al (11) reported the first case-control study on the CCND1 G870A polymorphism and colorectal cancer risk, but no significant differences in genotyping were observed in a population in the United States. To date, several molecular epidemiological investigations have been performed to evaluate the association between the CCND1 G870A polymorphism and colorectal cancer susceptibility, although the results were inconsistent. In the present investigation, a meta-analysis of published case-control studies was therefore performed to precisely assess the association between the CCND1 G870A polymorphism and the risk of colorectal cancer.

Materials and methods

This meta-analysis was designed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA Compliant) statement (12).

Search strategy

A comprehensive online search of the PubMed and Embase databases was performed for studies published up to June 1 2015 using the following search terms: ‘CCND1’, ‘cyclin D1’, ‘colorectal cancer’, ‘colon cancer’, ‘rectum cancer’ and ‘polymorphism’. Additional studies were searched for from the references of the retrieved studies, or from review articles on this topic. The following criteria were used to include identified studies in this meta-analysis: (i) a case-control study of the CCND1 G870A polymorphism and colorectal cancer risk; and (ii) sufficient data for estimating odds ratios (ORs) with 95% confidence intervals (CIs). In cases of partly or completely overlapping data, only the latest study, or the study with the larger sample, was included (13,14).

Data extraction

The following data were extracted from all selected studies independently by two investigators (Xiao-Ming Xu and Xiao-Bing Ni): the first author's name, publication data, country origin, racial descent of the study population (Asian, Caucasian or mixed), sources of the controls, genotype distribution, genotyping methods, adherence to the Hardy-Weinberg equilibrium (HWE), minor allele frequency (MAF) in controls, and tumor subtypes.

Statistical analysis

Five genotype models were evaluated based on ORs and 95% CIs to assess the potential association between CCND1 G870A polymorphisms and the risk of colorectal cancer: An allele contrast model (A vs. G), a pair of co-dominant models (AA vs. GG and GA vs. GG), a dominant model (GA+AA vs. GG) and a recessive model (AA vs. GG+GA). Subgroup analyses were performed according to ethnicity and control design. The study heterogeneity was assessed using Cochran's Q statistic and the I2 statistic (15). ORs were pooled using a random effects model with the inverse variance (I–V) method (or the DerSimonian and Laird method) when statistical heterogeneity was identified to exist (P<0.10 or I2>50%) (16); otherwise, a fixed effects model (the Mantel-Haenszel method) was adopted (17).

Funnel plots and Egger's linear regression method were used to assess any possible publication bias (18). Cumulative meta-analyses were also performed to identify possible trends in the pooled estimate according to the publication year (19).

All statistical analyses were performed using Stata® version 11.0 (Stata Corporation, College Station, TX, USA). A two-sided P<0.05 was considered to indicate a statistically significant value.

Results

Study characteristics

A total of 101 associated studies were searched. During the first step, while screening the title and screening for duplicates, 65 studies were excluded. Of the remaining 36 articles, 13 were excluded since two were reviews, two did not include sufficient genotype data, five were not focused on the polymorphism locus, and four were on other molecular studies. The flow chart of study selection is shown in Fig. 1. Ultimately, 23 published case-control studies met the inclusion criteria, including 6,320 patients with colorectal cancer and 8,352 controls (11,20–41). The genotype distribution in each study is shown in Table I. The diverse genotyping methods included polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), PCR-single strand conformation polymorphism, PCR Sequenase™ and TaqMan®. Overall, the MAF in controls ranged between 0.412 and 0.614 in Caucasians, and between 0.182 and 0.634 in Asians. In only one study did the control population significantly deviate from the HWE (29).

Figure 1.

Figure 1.

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Flow diagram of the study selection process. CCND1, cyclin D1.

Table I.

Characteristics of case-control studies included in the present meta-analysis.

Genotype distribution
Case Control
Authors Year Country/region Racial descent Source of controls Case Control GG GA AA GG GA AA Genotyping type P-value for HWEa MAF Type Refs.
Kong et al 2000 USA Caucasian Family-control 49 37 9 36 4 10 21 6 PCR-SSCP 0.366 0.446 HNPCC (11)
McKay et al 2000 UK Caucasian Population-control 100 101 25 58 17 34 50 17 PCR-RFLP 0.849 0.416 sCRC (20)
Kong et al 2001 USA Caucasian Healthy control 156 152 36 71 49 45 84 23 PCR-SSCP 0.112 0.428 sCRC (21)
Bala et al 2001 Finland Caucasian Family-control 146 186 50 70 26 47 97 42 PCR-SSCP 0.551 0.487 HNPCC (22)
Porter et al 2002 UK Caucasian Hospital-control 334 171 85 175 74 60 81 30 PCR-RFLP 0.768 0.412 CRC (23)
Caucasian Hospital-control 99 171 30 47 22 60 81 30 PCR-RFLP 0.768 0.412 HNPCC
Caucasian Hospital-control 128 171 34 65 29 60 81 30 PCR-RFLP 0.768 0.412 sCRC
Le Marchand et al 2003 USA Mixed Population-control 504 624 109 253 142 164 315 145 PCR-RFLP 0.792 0.485 CRC (24)
Caucasian Population-control 208 244 34 110 64 68 120 56 PCR-RFLP 0.792 0.475 CRC
Asian Population-control 296 380 75 143 78 96 195 89 PCR-RFLP 0.792 0.491 CRC
Grieu et al 2003 Australia Caucasian Hospital-control 569 327 142 313 114 90 158 79 PCR-SSCP 0.556 0.483 sCRC (25)
Hong et al 2005 Singapore Asian Healthy control 254 101 55 128 71 12 50 39 PCR-RFLP 0.505 0.634 sCRC (26)
Jiang et al 2006 India Asian Healthy control 301 291 46 130 125 56 145 90 PCR-RFLP 0.860 0.558 CRC (27)
Schernhammer et al 2006 USA Caucasian Population-control 610 1,237 125 311 174 264 593 380 TaqMan® 0.250 0.614 CRC (28)
Huang et al 2006 China Asian Hospital-control 831 1,052 126 411 294 199 464 389 PCR-RFLP 0.004 0.590 sCRC (29)
Probst-Hensch et al 2006 Singapore Asian Population-control 300 1,169 56 132 112 207 548 414 TaqMan® 0.272 0.589 CRC (30)
Krüger et al 2006 Germany Caucasian Population-control 406 245 141 188 77 73 121 51 PCR Sequenase™ 0.947 0.455 HNPCC (31)
Grünhage et al 2008 Germany Caucasian Hospital-control 194 218 37 93 64 48 109 61 PCR-RFLP 0.958 0.530 CRC (32)
Caucasian Hospital-control 98 218 13 50 35 48 109 61 PCR-RFLP 0.958 0.530 HNPCC
Caucasian Hospital-control 96 218 24 43 29 48 109 61 PCR-RFLP 0.958 0.530 sCRC
Tan et al 2008 Germany Caucasian Population-control 498 600 120 263 115 147 310 143 PCR-RFLP 0.414 0.497 CRC (33)
Forones et al 2008 Brazil Mixed Hospital-control 123 120 36 66 21 34 67 19 PCR-RFLP 0.141 0.438 CRC (34)
Talseth et al 2008 Australia Caucasian Hospital-control 157 153 34 78 45 42 80 31 TaqMan® 0.527 0.464 HNPCC (39)
Liu et al 2010 China Asian Population-control 373 838 66 187 120 160 429 249 PCR-RFLP 0.303 0.553 CRC (35)
Kanaan et al 2010 USA Caucasian Hospital-control 75 93 19 39 17 24 48 21 TaqMan® 0.748 0.484 sCRC (36)
Yaylim-Eraltan et al 2010 Turkey Caucasian Hospital-control 57 117 9 28 20 29 60 28 PCR-RFLP 0.781 0.496 CRC (37)
Jelonek et al 2010 Poland Caucasian Population-control 50 153 12 33 5 44 71 38 PCR-RFLP 0.383 0.480 CRC (38)
Sameer et al 2013 India Asian Healthy control 130 160 19 70 41 41 76 43 PCR-RFLP 0.528 0.506 CRC (40)
Govatati et al 2014 India Asian Healthy control 102 107 54 39 10 71 33 3 TaqMan® 0.719 0.182 CRC (41)
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HWE, Hardy-Weinberg equilibrium in control; MAF, minor allele frequency in controls; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; PCR-SSCP, polymerase chain reaction-single strand conformation polymorphism; CRC, colorectal cancer; HNPCC, hereditary non-polyposis colorectal cancer; sCRC, sporadic colorectal cancer.

Meta-analysis

The evaluation of the association between CCND1 G870A polymorphisms and colorectal cancer risk is shown in Table II. Overall, four of the genetic models revealed that the CCND1 G870A polymorphism was significantly associated with an increased risk of colorectal cancer (A vs. G, OR=1.09, 95% CI=1.00–1.18, I2=54.3%; GA vs. GG, OR=1.13, 95% CI=1.04–1.24, I2=18.2%; AA vs. GG, OR=1.17, 95% CI=1.00–1.38, I2=52.5%; and GA+AA vs. GG, OR=1.14, 95% CI=1.05–1.24, I2=33.8%; Fig. 2). Similarly, significant risk effects were detected in the subgroup analysis of patients with sporadic colorectal cancer (GA vs. GG, OR=1.21, 95% CI=1.04–1.42, I2=24.1%; GA+AA vs. GG, OR=1.18, 95% CI=1.02–1.37, I2=35.0%) and Caucasians (GA vs. GG, OR=1.14, 95% CI=1.02–1.28, I2=19.8%; GA+AA vs. GG, OR=1.14, 95% CI=1.02–1.27, I2=37.5%). Significantly increased risks were also detected in the stratified analysis of hospital-based studies and studies employing the PCR-PRFLP genotyping method (Table II).

Table II.

Summary of the ORs and 95% CIs of the CCND1 G870A polymorphism and colorectal cancer risk.

A vs. G GA vs. GG AA vs. GG GA+AA vs. GG AA vs. GG+GA
Parameter Na OR 95% CI P-value I2 OR 95% CI P-value I2 OR 95% CI P-value I2 OR 95% CI P-value I2 OR 95% CI P-value I2
Total 23 1.09 1.00–1.18 <0.01 54.3 1.13 1.04–1.24 <0.01 18.2 1.17 1.00–1.38 0.05 52.5 1.14 1.05–1.24 <0.01 33.8 1.08 0.95–1.23 0.23 54.7
HWE-yes 22 1.09 1.00–1.19 0.05 56.3 1.10 1.01–1.21 0.04 12.8 1.17 0.99–1.40 0.07 54.6 1.12 1.03–1.22 <0.01 34.2 1.10 0.95–1.26 0.20 55.1
Subtype
  HNPCC 6 1.06 0.86–1.31 0.59 59.5 0.98 0.79–1.22 0.88 37.3 1.13 0.72–1.76 0.60 58.9 1.08 0.78–1.51 0.63 54.8 1.08 0.87–1.35 0.48 37.1
  sCRC 8 1.06 0.91–1.24 0.46 59.0 1.21 1.04–1.42 0.02 24.1 1.13 0.82–1.56 0.45 59.9 1.18 1.02–1.37 0.03 35.0 1.04 0.80–1.35 0.77 62.2
Ethnicity
  Caucasian 15 1.09 0.98–1.22 0.10 56.1 1.14 1.02–1.28 0.02 19.8 1.19 0.95–1.90 0.13 56.7 1.14 1.02–1.27 0.02 37.5 1.08 0.89–1.30 0.43 57.2
  Asian 8 1.10 0.96–1.26 0.16 64.2 1.12 0.91–1.37 0.30 48.3 1.20 0.95–1.27 0.18 60.3 1.16 0.94–1.43 0.17 55.2 1.11 0.92–1.34 0.28 57.2
  Mixed 1 1.01 0.70–1.44 0.97 NA 0.93 0.52–1.66 0.81 NA 1.04 0.48–2.27 0.91 NA 0.96 0.55–1.67 0.87 NA 1.09 0.56–2.16 0.79 NA
Design
  Fam-B 2 0.80 0.61–1.06 0.12 0 1.02 0.38–2.75 0.97 66.9 0.60 0.34–1.08 0.09 0 0.92 0.38–2.23 0.86 616 0.69 0.42–1.15 0.16 0
  Heal-B 5 1.27 0.92–1.75 0.14 79.5 1.16 0.81–1.68 0.42 50.3 1.64 0.82–3.27 0.16 78.7 1.30 0.86–1.96 0.22 653 1.47 0.88–2.47 0.15 78.2
  Hosp-B 8 1.10 1.01–1.19 0.03 13.6 1.29 1.10–1.50 <0.01 0 1.24 1.05–1.48 <0.01 4.7 1.27 1.10–1.46 <0.01 0 1.03 0.90–1.17 0.69 33.3
  Pop-B 8 1.03 0.96–1.19 0.43 17.5 1.06 0.94–1.20 0.32 0.6 1.05 0.92–1.21 0.46 18.7 1.06 0.95–1.19 0.30 0 1.02 0.81–1.13 0.77 33.5
Genotyping type
  PCR-RFLP 13 1.10 1.04–1.18 <0.01 48.7 1.21 1.08–1.36 <0.01 13.0 1.24 1.09–1.41 <0.01 45.5 1.22 1.09–1.36 <0.01 25.1 1.08 0.98–1.19 0.11 49.2
  PCR-SSCP 4 1.04 0.76–1.41 0.81 73.1 1.08 0.85–1.37 0.53 42.7 1.05 0.54–2.05 0.87 74.1 1.07 0.75–1.54 0.71 51.4 0.99 0.52–1.91 0.98 80.5
  Taqman 5 1.11 0.94–1.32 0.22 54.1 1.09 0.91–1.30 0.36 0 1.09 0.89–1.33 0.42 45.9 1.10 0.93–1.30 0.27 14.9 1.04 0.89–1.21 0.65 49.5
  Others 1 0.87 0.70–1.09 0.23 NA 0.80 0.56–1.16 0.24 NA 0.78 0.50–1.23 0.28 NA 0.80 0.57–1.12 0.20 NA 0.89 0.60–1.32 0.57 NA
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Numbers of comparisons. NA, not available; HNPCC, hereditary non-polyposis colorectal cancer; sCRC, sporadic colorectal cancer; Fam-B, family-based; Heal-B, healthy-based; Hosp-B, hospital controls; Pop-B, population controls; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; PCR-SSCP, polymerase chain reaction-single strand conformation polymorphism.

Figure 2.

Figure 2.

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ORs and 95 % CIs for the association between the CCND1 G870A polymorphism and colorectal cancer risk in the GA+AA vs. GG model. CCND1, cyclin D1; OR, odds ratio; CI, confidence interval.

Publication bias

No publication bias was detected in any of the five genetic models. The shape of the funnel plots appeared to be symmetrical for all models (the GA+AA vs. GG model is shown in Fig. 3), and Egger's test results supported these findings (for A vs. G: P=0.34; for GA vs. GG: P=0.67; for AA vs. GG: P=0.53; for AA+GA vs. GG: P=0.47; and for AA vs. GG+GA: P=0.49).

Figure 3.

Figure 3.

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Funnel plot analysis to detect publication bias for the GA+AA vs. GG model of the CCND1 G870A polymorphism and colorectal cancer risk. or, odds ratio; s.e., standard error; CCND1, cyclin D1.

Sensitivity analysis and cumulative analysis

Sensitivity analyses were performed, and the exclusion of no single study qualitatively changed the pooled ORs, indicating that the results of the present meta-analysis were stable (the data for the GA+AA vs. GG model is shown in Fig. 4). Cumulative analyses according to the publication date revealed that the cancer risk increased gradually, and became positive, on inclusion of the study conducted by Talseth et al (39) in 2008 (the GA+AA vs. GG model is shown in Fig. 5).

Figure 4.

Figure 4.

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Sensitivity analysis through deleting each study to reflect the influence of the individual data-set to the pooled ORs in the GA+AA vs. GG model of the CCND1 G870A polymorphism and colorectal cancer risk. OR, odds ratio; CI, confidence interval; CCND1, cyclin D1.

Figure 5.

Figure 5.

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Cumulative meta-analyses according to publication year in the GA+AA vs. GG model of the CCND1 G870A polymorphism and colorectal cancer risk. OR, odds ratio; CI, confidence interval; CCND1, cyclin D1.

Discussion

CCND1 is located on chromosome 11q13, and encodes a critical cell cycle regulatory protein of 295 amino acids. CCND1 regulates the transition from the G1 to the S phase during cell division. High levels of activity of CCND1 result in premature cell passage through the G1-S transition, leading to an extension of non-repaired DNA damage and the accumulation of genetic mistakes (42). Overexpression of CCND1 has been detected in several cancer types, which is also regarded as a risk factor for cancer development. Of the SNPs in CCND1, the G-to-A mutation is the most common, and does not result in an amino acid alteration in the protein sequence. However, the A allele change does lead to an alternatively spliced transcript of CCND1, with a longer half-life compared with the G allele, which facilitates the passage of the variant cell through the G1-S checkpoint and rapid proliferation, ultimately resulting in cancer development (43). Previous studies have shown that the A allele may be associated with an increased risk of breast, prostate, esophageal and other cancer types in different ethnicities (44–46).

In 2000, the first case-control study performed by McKay et al (20) failed to reveal any significant association between the CCND1 G870A polymorphism and the risk of colorectal cancer in Caucasians. To date, conflicting data about the association between the CCND1 G870A polymorphism and colorectal cancer susceptibility exist. Kong et al (21) identified that the risk of developing colorectal cancer was 3-fold higher in Caucasians with a homozygous A allele (OR=2.68, 95% CI=1.38–5.19). The study by Jiang et al (27) suggested that the AA genotype may increase the colorectal cancer risk compared with the GG+AG genotype (OR=1.56, 95% CI=1.10–2.21) in an Indian population. Huang et al (29) also identified a significant association between the CCND1 G870A polymorphism and the risk of colorectal cancer in young Chinese patients. Notably, the mechanism of the G870A polymorphism differs according to ethnicity. Porter et al (23) demonstrated an increased risk of familiar colorectal cancer of almost 2-fold (for GA+AA vs. GG: OR=1.7, 95% CI=1.1–2.7) although the authors did not find any significant association with sporadic colorectal cancer in Caucasians. Le Marchand et al (24) reported a significantly increased risk in Hawaiian individuals with a heterozygous GA genotype (OR=3.9, 95% CI=1.2–13.2), and a marginal risk in Caucasians with a homozygous AA genotype (OR=2.1, 95% CI=1.0–4.3), although the authors did not find any significant association in a Japanese population. However, the studies by Bala, Schernhammer, Krüger and other research groups (22,25,28,31,33–36) failed to identify any significant association between the CCND1 G870A polymorphism and colorectal cancer. By contrast, several studies revealed that the A allele exerts a protective function in the development of colorectal cancer (26,30,37,38). The present meta-analysis, comprising 23 case control studies with 6,320 patients with colorectal cancer and 8,252 controls, explored the association between an increased risk of colorectal cancer and the CCND1 G870A polymorphism. The findings suggested that CCND1 exerts an important role in the development of colorectal cancer, particularly in Caucasians and in the development of sporadic colorectal cancer.

Several limitations of the present analysis should be acknowledged. First, the results are based on the unadjusted estimates, without the original data from the selected studies, and lack information on certain co-variables, including diet, smoking, drinking and other environmental factors. Secondly, small numbers of patients were included in the cancer subgroups, including cancer location and familiar hereditary, which prevented more precise conclusions from being drawn. The actual association could therefore be biased, and the analysis may not have enough statistical power with the current small sample size. Thirdly, the controls in several of the studies were hospital-based populations with other diseases, which could also result in a certain selection bias. Finally, the majority of the included studies were performed in Caucasian and Asian populations, without any reported studies in African populations; therefore, ethnicity may also result in a certain bias. Despite these limitations, the present meta-analysis included 23 published articles with the largest sample sizes and latest data. A cumulative analysis also demonstrated that the results of our meta-analysis were stable, which further confirm the reliability and validity of the present study.

In conclusion, the present meta-analysis suggested that the CCND1 G870A polymorphism may be associated with an increased risk of the development of colorectal cancer. Considering the limitations due to the small sample size, larger, well-designed case-control studies are required to further validate these findings.

Acknowledgements

The present study was supported by grant no. D20142102 from the Ministry of Education of Hubei Province.

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