Cyclin D1 polymorphism and risk for squamous cell carcinoma of the head and neck: a case-control study

Abstract

A G-->A polymorphism (G870A) in exon 4 of the cyclin D1 (CCND1) gene creates an alternative splice site in its mRNA, encoding a protein with an altered C-terminal domain. It has been suggested that DNA damage in cells with the A allele bypasses the G(1)/S checkpoint of the cell cycle more easily than damage in cells without the A allele. Because CCND1 plays a critical role in cell cycle control and reduced DNA repair capacity is associated with an increased risk for squamous cell carcinoma of the head and neck (SCCHN), we hypothesize that this CCND1 polymorphism modulates individual susceptibility to SCCHN. To test this hypothesis we evaluated the frequency of the polymorphism in a hospital-based case-control study of 233 newly diagnosed SCCHN patients and 248 non-cancer controls. The cases and controls were frequency matched by age (+/-5 years), sex and tobacco use. All subjects were non-Hispanic whites. We found that the A allele frequency was slightly higher in the cases (0.485) than in the controls (0.425), but the difference was borderline statistically significant (P = 0.064). The frequencies of the CCND1 AA, GA and GG genotypes were 23.6, 49.8 and 26.6%, respectively, in cases and 16.5, 52.5 and 31.5%, respectively, in controls. Multivariate logistic regression analysis adjusting for age (in years), sex, smoking and alcohol use was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Compared with the wild-type CCND1 GG, the CCND1 A G genotype was associated with a non-significantly increased risk (adjusted OR 1.15, 95% CI 0.75-1.76), but the CCND1 AA genotype was associated with a significantly increased risk (adjusted OR 1.77, 95% CI 1.04-3.02) for SCCHN. Results from a trend test using a logistic regression model were statistically significant (P = 0.044). Among the cases the mean age of onset was 59.0, 56.8 and 55.5 years for the GG, GA and AA genotypes, respectively. In the stratification analysis the CCND1 AA variant genotype was associated with a >3-fold increased risk in individuals who were </=50 years old (OR 3.18, 95% CI 1.19-8.46), females (3.57, 1.26-10.0), non-smokers (3.71, 1.37-10.1) and non-alcohol users (4.76, 1.61-14.0). These results suggest that the CCND1 polymorphism is associated with early onset of SCCHN and contributes to susceptibility to SCCHN in this population.

Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism

“…The possible interaction of the A allele with other genetic or environmental factors may partially explain these discrepancies. 30 Although a significant association was observed between the AA genotype and advanced-stage or high-grade PCa patients compared to controls (Table III), no significant differences in genotype frequency were found between the 3 tumor grades or between localized and metastatic tumors. Therefore, the relation between the A870G polymorphism and progression and/or advanced stage of PCa remains to be elucidated by further studies.…”

“…Although the CCND1 polymorphism was not associated with the onset of colorectal cancer in a small population, 29 Zheng et al 30 reported that the AA genotype was associated with an increased risk of colorectal cancer at a younger age. Furthermore, patients with at least 1 A allele developed colorectal cancer at an average of 11 years earlier than those without the A allele, suggesting a dominant effect of this allele on tumor onset in hereditary nonpolyposis colorectal cancer.…”

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

“…Previous studies have had inconsistent results for an association of the CCND1 A870G polymorphism with bladder cancer (Cortessis et al, 2003;Wang et al, 2003b;Berman et al, 2004;Ito et al, 2004), endometrial cancer (Kang et al, 2005), breast cancer (Grieu et al, 2003;Krippl et al, 2003;Shu et al, 2005), head and neck cancer (Zheng et al, 2001), gastric and oesophageal cancer (Wang et al, 2003c;Zhang et al, 2003a), hepatocellular carcinoma (Zhang et al, 2003b), lung cancer (Qiuling et al, 2003), and prostate cancer (Koike et al, 2003;Wang et al, 2003a). The strongest evidence, to date, has linked the CCND1 A870G polymorphism with an increased risk of colorectal cancer and adenoma in many (Kong et al, 2000(Kong et al, , 2001Bala and Peltomaki, 2001;Porter et al, 2002) though not all studies (McKay et al, 2000).…”

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

“…15 It was proposed initially that DNA-damaged cells in individuals with the A allele may bypass the G 1 /S checkpoint, resulting in the accumulation of an increased proportion of cells with DNA damage and genetic alterations. 26 Subsequent studies have demonstrated an association between the CCND1 A/A genotype and increased risk for various human malignancies, [27][28][29][30][31][32][33][34] including premalignant lesions of the upper aerodigestive tract 35 and colon. 36 Two studies evaluated the CCND1 G870A polymorphism in esophageal squamous cell carcinoma in the Chinese population.…”