Candidate molecular markers for oral precancer and cancer

Abstract

9598 Background: Alterations in expression of cell cycle regulators and retinoid receptors are implicated in human cancers. The development of oral cancer is a multistep process. We hypothesized that altered expression of retinoic acid receptors (RARα, β, γ) and retinoid X receptor RXRα and their relationship with cell cycle regulators (p53, cyclinD1, pRb, p16, p21) is associated with development, progression and prognosis of oral cancer. Methods: Immunohistochemical analysis of RARα, β, γ and RXRα proteins was carried out on serial sections from 220 oral squamous cell carcinomas (OSCCs), 98 potentially malignant lesions (61 hyperplasias, 37 dysplasias) and 81 matched histologically normal oral tissues and correlated with expression of cell cycle regulators p53, CyclinD1, pRb, p16 and p21 in these tissues as well as in tumor free margins and with clinicopathological parameters. The prognostic relevance of these factors was assessed in 100 of these SCC patients who were followed-up for a maximum period of 94 months. Results: Expression of retinoid receptors RARβ, RARγ, RXRα and cell cycle regulators p16, pRb and p21 was decreased in majority of oral SCCs as well as in potentially malignant lesions. Accumulation of p53 in tumor free margins was associated with adverse prognosis. Multivariate stepwise logistic regression analysis indicated that the significant predictors of transition from: normal to potentially malignant stage were p16, RARβ and RARα +/p21-; hyperplasia to dysplasia was RARα +/ p53+ and potentially malignant to malignant phenotype were cyclinD1 and RARα +. Multivariate analysis using Cox’s proportional Hazard’s model showed that RARα +/p21- phenotype was associated with reduced disease free survival. Conclusions: Analysis of alterations in expression of retinoid receptors at the protein level at different stages in development and progression of oral SCC and their interactions with cell cycle regulators in multistep oral tumorigenesis underscored, for the first time, their diagnostic and prognostic significance for this disease. No significant financial relationships to disclose.