Alterations in cyclin D1 expression in esophageal squamous cell carcinoma in the Indian population

Purpose: The p16/cyclin D1/pRb pathway plays a critical role in tumourigene sis. We recently reported alterations in expression of tumour suppressor ge ne products, p16 and pRb in esophageal cancer. Knowledge of alterations in cyclin D1, a vital component of this pathway in esophageal carcinomas from the Indian subcontinent, where the etiology and pathogenesis may be confoun ded by various unique dietary and environmental factors, is presently scant y. In order to bridge the gap between the accentuating incidence of esophag eal cancer and aberrations in the components of this vital pathway, we anal ysed cyclin D1 expression in esophageal squamous cell carcinoma in the Indi an population, Method: Immunohistochemical analysis of cyclin Dl expression was carried out in paraffin-embedded sections of surgically resected esoph ageal squamous cell carcinomas (ESCC) (70 patients) and matched with histop athologically normal esophageal tissues from a distant site. The findings w ere correlated with clinicopathological parameters. Results: Overexpression of cyclin D1 was observed in the tumour nuclei in 41 out of 70 (59%) patie nts. We found concomitant alterations in 16 and cyclin D1 (p16(-)/CycD1(+) phenotype) in 16 of the 70 patients (23%), while alterations of pRb and cyc lin D1 (pRb(-)/CycD1(+)) were observed in 36 of the 70 (51%) patients of ES CCs. Cyclin D1 overexpression was significantly associated with the loss of p16 immunoreactivity (P=0.005). The pRb(-) and p16(-)/ pRb(-)/Cyc D+ pheno types showed significant association with differentiation of the tumour (P = 0.005, 0.05, respectively). Kaplan-Meier analysis for disease recurrence showed increased disease recurrence in cyclin D1 overexpressed patients. Me dian time to disease recurrence in the cyclin D1(+) group was 15 months as against 18 months observed in the cyclin D1(-) patients (P = 0.067; log-ran k test). Conclusion: Alterations in at least one of the components of the p 16/cyclin D1/pRb pathway in majority of the 70 patients analysed herein. an d concomitant alterations in all the three proteins in 19 patients (35%) un derscore the critical role of this pathway in esophageal tumourigenesis. Th e results of the present study taken together with our previous findings on p16 and pRb alterations in ESCCs suggest that these alterations are not mu tually exclusive and may cooperatively provide greater tumour growth advant age. The prc,gnostic significance of alterations in the expression of these components cyclin D1, p16, and pRb remains to be established in a larger c ohort.