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Alterations in cyclin D1 expression in esophageal squamous cell carcinoma in the Indian population
1Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Purpose:
The p16/cyclin D1/pRb pathway plays a critical role in tumourigenesis. We recently reported alterations in expression of tumour suppressor gene 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 confounded by various unique dietary and environmental factors, is presently scanty. In order to bridge the gap between the accentuating incidence of esophageal cancer and aberrations in the components of this vital pathway, we analysed cyclin D1 expression in esophageal squamous cell carcinoma in the Indian population.
Method:
Immunohistochemical analysis of cyclin D1 expression was carried out in paraffin-embedded sections of surgically resected esophageal squamous cell carcinomas (ESCC) (70 patients) and matched with histopathologically normal esophageal tissues from a distant site. The findings were correlated with clinicopathological parameters.
Results:
Overexpression of cyclin D1 was observed in the tumour nuclei in 41 out of 70 (59%) patients. We found concomitant alterations in 16 and cyclin D1 (p16-/CycD1+ phenotype) in 16 of the 70 patients (23%), while alterations of pRb and cyclin D1 (pRb-/CycD1+) were observed in 36 of the 70 (51%) patients of ESCCs. Cyclin D1 overexpression was significantly associated with the loss of p16 immunoreactivity (P = 0.005). The pRb- and p16-/pRb-/Cyc D+ phenotypes 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. Median 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-rank test).
Conclusion:
Alterations in at least one of the components of the p16/cyclin D1/pRb pathway in majority of the 70 patients analysed herein, and concomitant alterations in all the three proteins in 19 patients (35%) underscore the critical role of this pathway in esophageal tumourigenesis. The results of the present study taken together with our previous findings on p16 and pRb alterations in ESCCs suggest that these alterations are not mutually exclusive and may cooperatively provide greater tumour growth advantage. The prognostic significance of alterations in the expression of these components cyclin D1, p16, and pRb remains to be established in a larger cohort.
Insights
Cyclin D1 overexpression is common in Indian esophageal squamous cell carcinoma (ESCC), often occurring with p16 and pRb pathway alterations. These changes may drive tumor growth and impact disease recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The p16/cyclin D1/pRb pathway is crucial in tumor development.
- Previous studies reported p16 and pRb alterations in esophageal cancer.
- Limited data exists on cyclin D1 in Indian esophageal carcinomas due to unique factors.
Purpose of the Study:
- To investigate cyclin D1 expression in Indian esophageal squamous cell carcinoma (ESCC).
- To correlate cyclin D1 alterations with p16 and pRb pathway components.
- To assess the association of cyclin D1 expression with clinicopathological parameters and disease recurrence.
Main Methods:
- Immunohistochemical analysis of cyclin D1 in 70 ESCC tissues and matched normal esophageal tissues.
- Correlation of cyclin D1 expression with p16, pRb, and clinicopathological parameters.
- Kaplan-Meier analysis to evaluate disease recurrence in relation to cyclin D1 status.
Main Results:
- Cyclin D1 overexpression was found in 59% of ESCC cases.
- Concomitant alterations in p16/cyclin D1 (23%) and pRb/cyclin D1 (51%) were observed.
- Cyclin D1 overexpression correlated significantly with loss of p16 and tumor differentiation.
- Increased disease recurrence was noted in patients with cyclin D1 overexpression.
Conclusions:
- Alterations in the p16/cyclin D1/pRb pathway are prevalent in Indian ESCC.
- Coexisting alterations in these proteins may enhance tumor growth.
- Further studies on a larger cohort are needed to establish the prognostic significance of these pathway alterations.