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Carcinogenesis Advance Access originally published online on April 25, 2006
Carcinogenesis 2006 27(10):2034-2037; doi:10.1093/carcin/bgl048
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Cyclin D1 gene polymorphism as a risk factor for oral premalignant lesions

Maosheng Huang, Margaret R. Spitz, Jian Gu, J.Jack Lee1, Jie Lin, Scott M.Lippman2 and Xifeng Wu*

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA
1 Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA
2 Department of Thoracic/Head and Neck Oncology, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA

*To whom correspondence should be addressed at: Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA. Tel: +1 713 745 2485; Fax: +1 713 792 4657; Email: xwu{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background: Deregulation of cell cycle plays an important role in tumorigenesis. Cyclin D1 gene (CCND1) is a key regulator of the G1 phase of the cell cycle. Methods: In this case–control study of 115 oral premalignant lesion (OPL) patients and 230 controls, we genotyped the CCND1 single nucleotide polymorphism (SNP) at the exon 4 splice site (G870A) and determined the association of this SNP with the risk of developing OPLs. Results: We found significant associations between the heterozygous variant allele (GA), the homozygous variant allele (AA) and OPL risk, with adjusted odds ratios (ORs) of 1.91 [95% confidenc interval (CI), 1.05–3.48] and 2.38 (95% CI, 1.16–4.87), respectively. The OR for individuals with at least one variant allele was 2.04 (95% CI, 1.15–3.60). When further stratified analyses were performed, the increased risk was more evident in younger individuals (OR = 2.82; 95% CI, 1.32–6.02), in men (OR = 2.97; 95%CI, 1.31–6.71) and in never smokers (OR = 2.92; 95% CI, 1.09–7.82). Finally, we found joint effects between the variant alleles and the smoking status. Using never smokers with the wild-type (GG) genotypes as the reference group, the ORs for never smokers with the variant genotypes (G/A + A/A), smokers with the G/G genotype and smokers with the G/A + A/A genotypes were 2.92 (1.09–7.82), 3.95 (1.36–11.5) and 7.01 (2.68–18.4), respectively. Conclusion: Our results suggest that the CCND1 G870A SNP may contribute to genetic susceptibility to OPLs and involve in oral cancer development.

Abbreviations: CDK, cyclin-dependent kinase; CCND1, cyclin D1 gene; HWE, Hardy–Weinberg equilibrium; OPL, oral premalignant lesions


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Oral leukoplakia, oral submucous fibrosis and erythroplakia are the three major forms of oral premalignant lesions (OPLs) (1). The development of these lesions as the results of carcinogenic exposures may cause simultaneous genetic defects to the upper aerodigestive tract epithelium at different stages of carcinogenesis (2–4). Individuals with these lesions are at a high risk for developing oral cancer. The overall malignant transformation rate for dysplastic lesions depends on the length of follow-up and varies from 11 to 36% (4,5). According to our data, during a follow-up of 7 years, 31.4% of OPL patients developed cancers in the upper aerodigestive tract and the overall cancer incidence is 5.7% per year (6). Tobacco chewing, tobacco smoking and alcohol drinking are major risk factors for OPLs (7–9). In addition, the inherited genetic susceptibility may also play an important role in oral tumorigenesis (10).

The cell cycle deregulation is linked to tumorigenesis. Specifically, the deregulation of G1 -> S phase progression of the cell cycle was a common target in malignant transformation (11,12). The transition from G1 into S phase is regulated by cyclin-dependent kinases (CDKs), Cdk4 and Cdk6, in protein complexes with cyclin D1. Cyclin D1 is a key regulator of the G1 phase of cell cycle progression. Cyclin D1 catalyzes the phosphorylation of the tumor suppressor protein retinoblastoma (RB). The phosphorylation of RB releases the transcriptional factor E2F, which then activates a number of downstream genes necessary for cell cycle progression. Therefore, inhibition of cyclin D1 results in cell cycle arrest, whereas overexpression of the protein accelerates the G1 phase transition (11,13). Cyclin D1 gene, CCND1, is located on chromosome 11q13. Aberrations of CCND1, such as chromosome amplification, translocations and inversions, are common in human cancers (14,15). In addition, many studies suggested that a common SNP in the CCND1 gene, the G870A at the exon 4 splice site, was associated with the risk of several malignancies (16–21). The G870A SNP at the exon 4 splice site has been shown to increase the frequency of alternative splicing and lead to an increase in the half-life of the protein (21,22). It has been suggested that cells from subjects with the variant A-allele may bypass the G1/S checkpoint more easily than cells with the wild-type allele, resulting in an increased proportion of cells with DNA damage in subjects carrying the variant allele (21,23).

There have not been any reports about the association of CCND1 genetic polymorphisms with OPLs. In this case–control study, we estimated the G870A allele frequencies in OPL cases and controls and determined the association between the G870A SNP and the risk of developing OPLs.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study subjects
A total of 115 OPL patients were identified at The University of Texas M.D. Anderson Cancer Center from 1997 to 2005 before they were randomized into a chemoprevention trial (5). The inclusion criteria for cases were the presence of histologically confirmed OPL (leukoplakia and/or erythroplakia). As OPL patients were participants of a chemoprevention trial, only those ages ≥18 years were enrolled. Enrollment into the clinical trial also excluded patients with acute intercurrent illnesses or infections and patients who had retinoid or carotenoid therapy within 3 months prior to study entry. Patients with prior history of cancer (except non-melanoma skin cancer) that had been treated within the preceding 2 years were also excluded. A self-administered questionnaire was used to collect epidemiological data, including demographical information and tobacco use history. Before the subjects were randomized into the chemoprevention trial, blood samples were obtained in heparinized tubes for molecular analyses. Healthy controls who (n = 230) had no history of cancer were recruited from the Kelsey–Seybold clinics, the largest multispecialty managed-care organization consisting of more than 300 physicians and 23 clinics in the Houston metropolitan area. The potential controls were identified by reviewing short survey forms distributed to patients coming to the clinic for annual health check-ups. Controls had no prior history of cancer (except non-melanoma skin cancer) and were frequency matched to the OPL cases by age (±5 years), sex and ethnicity. Epidemiologic questionnaire data were obtained through in-person interview for the controls. After the interview, participants were asked to donate a blood sample (40 ml) for molecular analysis. Controls were recruited during 1999–2005. For both cases and controls, informed consent was obtained from each participant and approval for conducting human subjects research was obtained from the M.D. Anderson and the Kelsey–Seybold institutional review boards. An individual who had never smoked or had smoked less than 100 cigarettes in his or her lifetime was defined as a never smoker. A former smoker was a person who had quit smoking at least 1 year prior to diagnosis (cases) or who had quit smoking at least 1 year prior to the interview (controls). A current smoker was someone who was currently smoking or who had stopped <1 year prior to being diagnosed (cases) or interview (controls). Current and former smokers were defined as ever smokers.

Genotyping
Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion, followed by isopropanol extraction and ethanol precipitation. DNA samples were stored at –80°C. The CCND1 G870A genotyping was performed using the TaqMan SNP assay. The probes were labeled fluorescently with either 6-FAM or VIC on the 5' end and a non-fluorescent minor groove binder (MGB) quencher on the 3' end (Applied Biosystems). The primer and probe sequences used were as follows: 5'-ACGCTTCCTCTCCAGAGTGATC (forward primer), 5'-AGGCTGCCTGGGACATCA (reverse primer), VIC-TGACCCgGTAAGTGAG-MGB (G allele) and 6FAM-TGACCCaGTAAGTGAG-MGB (A allele). Typical amplification mixes (5 µl) contained sample DNA (5 ng), 1x TaqMan buffer A, 200 µM dNTPs, 5 mM MgCl2, 0.65 U of AmpliTaq Gold, 900 nM each primer and 200 nM each probe. The reactions were carried out on the dual 384-well GeneAmp PCR System 9700. The thermal conditions were 95°C for 10 min followed by 50 cycles of 92°C for 30 s and 60°C for 1 min. The reacted plates were then read using the ABI Prism 7900HT Sequence Detection System. The analyzed fluorescence results were then auto called into genotypes using the built-in software of the system.

Statistical analysis
All statistical analyses were performed with the Stata 8.0 statistical software package (Stata Corporation, College Station, TX). Pearson's {chi}2-test was used to compare the distribution of selected characteristic variables including gender, ethnicity, smoking status and the CCND1 genotypes between the cases and the controls. The student's t-test was used to test for differences in the distribution of age between the two groups. Hardy–Weinberg equilibrium (HWE) was tested using the goodness-of-fit {chi}2-test to compare the observed allele frequencies with the expected frequencies in control subjects. Unconditional multivariate logistic regression models were used to calculate odds ratio [OR; 95% confidence interval (CI)] associated with the CCND1 genotypes while controlling for possible confounding factors such as age, gender, ethnicity and smoking status. Interaction between variables was assessed by adding a product term into the logistic regression model. All statistical tests were two-sided with a significance level of 0.05.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
There were no statistically significant differences between 115 OPL cases and 230 healthy controls in terms of age, gender and ethnicity (Table I). The mean age of controls (58.88 ± 11.24 years) was slightly older than that of cases (57.61 ± 12.49 years), but the difference was not significant (P = 0.340). As expected, there was a significant difference in smoking status between cases and controls, with significantly more ever smokers in the cases (67.83%) than in the controls (44.35%) (P < 0.001) (Table I).


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  		Table I Distribution of host characteristics in cases and controls

 
In Caucasians, the variant A-allele frequency was 0.420 in the controls and 0.526 among the cases. The genotype distribution was in agreement with that expected under the HWE among both the controls and the cases (P = 0.64 and 0.34, respectively). For African-Americans and Mexican Americans, estimation of variant allele frequency and assessment of HWE were unreliable due to the small sample size (data not shown).

Both the A/G and A/A genotypes were more common in the cases than in the controls (52.94 versus 47.82%, P = 0.035; and 25.49 versus 18.70%, P = 0.018, respectively). After adjusting by age, gender, ethnicity and smoking status, compared to individuals with the wild-type G/G genotype, individuals with the A/G and A/A genotype exhibited significantly increased OPL risks with adjusted ORs of 1.91 (95% CI, 1.05–3.48) and 2.38 (95% CI, 1.16–4.87), respectively. Combining the heterozygous AG and homozygous variant AA genotypes generated an OR of 2.04 (95% CI, 1.15–3.60). When further stratified analyses were performed, we found that the increased risk conferred by the variant genotypes (G/A + A/A) was more evident in younger individuals (OR = 2.82; 95% CI, 1.32–6.02), in males (OR = 2.97; 95% CI, 1.31–6.71) and in never smokers (OR = 2.92; 95% CI, 1.09–7.82) (Table II).


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  		Table II Risk estimates of the CCND1 genotypes by age, gender and smoking status

 
We then evaluated the joint effect between the variant alleles of CCND1 and smoking status in modulating OPL risk. Using never smokers with the wild-type (GG) genotypes as the reference group, the ORs for never smokers with the variant genotypes (G/A + A/A), smokers with the G/G genotype and smokers with the G/A + A/A genotypes were 2.92 (1.09–7.82), 3.95 (1.36–11.5) and 7.01 (2.68–18.4), respectively. However, the interaction did not reach statistical significance (P = 0.535 ) (Table III).


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  		Table III Joint effect between genotypes of CCND1 polymorphism and smoking status

 

   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Given that OPL patients have a high risk of oral cancer development, identifying subgroups at high risks of premalignancy development is critical for oral cancer prevention. Our results suggest that individuals with one or more copies of the CCND1 G870A variant A-allele are at an increased risk of OPL development. Several previous studies have reported associations between the CCND1 G870A SNP and increased risks for a number of solid tumors, including cancers of colon, lung, skin, head and neck, prostate, bladder, renal and esophagus (17–18,21,23–33). To our knowledge, the current study is the first to demonstrate that individuals with the CCND1 G870A variant genotype are at an increased risk for OPLs, supporting the hypothesis that this polymorphism may be a susceptibility factor in the molecular progression of oral cancer.

The CCND1 gene encodes protein cyclin D1, which regulates cell cycle progression. Cyclin D1 is activated by cyclin-dependent kinases 4 and 6 (34). This complex inactivates the RB protein, resulting in the transition from the G1 to S phase (35) and allowing DNA replication. In animal models, deregulated cyclin D1 expression has been associated with increased genetic instability, accelerated cell proliferation and promotion of tumorigenesis (36–38). Mice deficient in cyclin D1 are resistant to cancer development (39). The G870 SNP is located at the splice donor site between exon 4 and intron 4 boundary. The variant A-allele preferentially encodes the altered transcript b, even in the heterozygous state (21,40). Compared to the commonly studied cyclin D1 transcript a, transcript b encodes a protein with longer half-life, resulting in the accumulation of cyclin D1 in the cell and leading to the passing of the G1/S phase checkpoint without sufficient control in the defective cells.

Nishimoto et al. (25) observed that CCND1 G870A variant allele was a risk factor for squamous cell carcinoma of the upper aerodigestive tract in non-alcoholics and non-smokers. Carlos de Vicente et al. (41) recently showed that cyclin D1 might be a useful prognostic factor for oral squamous cell carcinoma. Our study indicated that cyclin D1 might be involved in the early carcinogenesis of oral cancer. These data strongly support that cyclin D1 may be involved in the initiation and development of oral cancer.

In stratified analysis, we observed that the increased risk was only evident in younger individuals (≤60 years old), in males and in never smokers. The observation that genetic effect was only evident in never smokers supports the notion that heavy carcinogen exposure may overwhelm genetic effects (42,43). Younger individuals tend to smoke shorter duration than older subjects, thus the age differences observed in this study may be partly attributed to differences in smoke exposure between the two age groups. Low statistical power may be an explanation for the lack of association in females due to the relatively small sample number of females. Consistent with our results, Shi et al. (24) also noted that the CCND1 G870A variant genotype (A/A) was associated with a significantly increased risk for lung cancer and the effects were more evident in younger subjects (<50 years) and in males.

This study has several limitations. This is a hospital-based case–control study, which may subject to potential selection bias. However, as this study tested a genotype-driven hypothesis rather than an environment-driven hypothesis, the matching of cases and controls in terms of residency is less of a concern. We have previously provided support to the validity of recruiting controls from large multispecialty care organization in molecular epidemiologic studies of cancer (44). Data collected by self-administered questionnaire and in-person interview may produce differential bias in risk assessment. However, in this study, the influence should be minimal because we only used demographic information and smoking status data collected by questionnaire. Subjects should be able to report consistent information in both self-administered questionnaire and in-person interview in terms of demographic characteristics (age, gender, ethnicity) and smoking status (never, ever). The relatively small sample size limits the power to detect gene–environment interactions. Future larger study is warranted to confirm the findings.

In conclusion, this is the first study to demonstrate the association between the CCND1 polymorphism and the risk of premalignant lesions. Our results suggest that the CCND1 G870A SNP may be invovled in the early carcinogeneis of oral cancer.


   Acknowledgments
 
This study was supported by National Cancer Institute Grants CA 106451 and CA097007. Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received January 1, 2006; revised April 6, 2006; accepted April 11, 2006.


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