CCND1 polymorphisms (A870G and C1722G) modulate its protein expression and survival in oral carcinoma.

Cyclin D1 is an essential regulator of the G1 phase of the cell cycle progression and plays an important role in the transition of the cell from the G1 phase to the S phase of the cell cycle. Overexpression of cyclin D1 is a frequently observed feature of human cancers of diverse histological origin. Recently, we have reported overexpression of cyclin D1 in oral carcinoma. However, the underlying mechanism leading to this aberrant expression remains poorly understood. In this study, we have investigated the role of CCND1 A870G and C1722G polymorphisms on cyclin D1 expression and prognosis in a relatively homogenous population of 178 oral squamous cell carcinoma patients by PCR-SSCP, RFLP, RT-PCR and immunohistochemical methods. Genotype frequencies of both the polymorphisms were conformed to Hardy-Weinberg equilibrium. CCND1 A870G (p=0.004) and C1722G (p=0.012) polymorphisms were significantly associated with cyclin D1 expression. Kaplan-Meier estimates revealed that CCND1 genotypes A870G 'GG' (p=0.012) and C1722G 'CC' (p=0.021) could predict the poor survival of the patients. In multivariate analysis, CCND1 A870G genotype combination (p=0.024, HR - 1.74 (1.08-2.81)) and cyclin D1 expression (p=0.025, HR - 1.72 (1.07-2.77)) were independent predictors of survival in this patient cohort. Our results thus demonstrate, CCND1 polymorphisms stand-in as cis-acting regulatory elements modulating its expression and cyclin D1 genotype and phenotype could provide valuable additional information regarding prognosis of oral cancer patients.