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

A G -->A polymorphism (G870A) in exon 4 of the cyclin D1 (CCND1) gene creat es an alternative splice site in its mRNA, encoding a protein with an alter ed C-terminal domain. It has been suggested that DNA damage in cells with t he A allele bypasses the G(1)/S checkpoint of the cell cycle more easily th an damage in cells without the A, allele. Because CCND1 plays a critical ro le 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 suscepti bility 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 noncancer controls. The cases and controls were freq uency matched by age (+/-5 years), sex and tobacco use. All subjects were n on-Hispanic whites. We found that the A allele frequency was slightly highe r 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 C CND1 AA, GA and GG genotypes were 23.6, 49.8 and 26.6%, respectively, in ca ses and 16.5, 52.5 and 31.5%, respectively, in controls. Multivariate logis tic regression analysis adjusting for age (in years), sex, smoking and alco hol use was performed to calculate odds ratios (OR) and 95% confidence inte rvals (CI). Compared with the wild-type CCND1 GG, the CCND1 A G genotype wa s 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 significant ly increased risk (adjusted OR 1.77, 95% CI 1.04-3.02) for SCCHN. Results f rom a trend test using a logistic regression model were statistically signi ficant (P = 0.044). Among the cases the mean age of onset was 59.0, 56.8 an d 55.5 years for the GG, GA and AA genotypes, respectively. In the stratifi cation analysis the CCNDI AA variant genotype was associated with a >3-fold increased risk in individuals who were less than or equal to 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 t hat the CCND1 polymorphism is associated with early onset of SCCHN and cont ributes to susceptibility to SCCHN in this population.