Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Microsatellite alterations at 3p, 2p and 16 q loci in Esophageal Squamous Cell Carcinoma: Association with cell cycle regulatory proteins

R Mathew 1, S Arora 1, AS Ebrahim 1, M Mathur 2, TK Chattopadhyay 3, R Ralhan 1

1 Dept Biochemistry,, 2 Dept Pathology,, 3 Dept Gastroenterology Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India,

AIM: To investigate the association between Microsatellite instability (MSI) as a determinant of propensity with aberrations in major cell cycle regulatory proteins and histopathological parameters. METHODS: Microsatellite alterations have been analyzed by polymerase chain reaction (PCR), in 25 ESCC cases in Indian population and were categorized as Loss of heterozygosity (LOH) and Replication error repeat (RER). Protein alterations have been analyzed using immunohistochemical technique and the associations between Replication Error phenotypes(RER positive) and cell cycle regulatory protein status were estimated by chi square and FisherÂ’s exact analyses. Survival analyses have been carried out by Kaplan Meier analysis and log rank test. RESULTS: Analyses at these loci demonstrated moderate microsatellite alterations, suggesting the involvement of microsatellite instability in esophageal tumorigenesis in a subset of Indian population. MSI, defined as RER in at least two or more of the loci studied was observed in a significant subset (33%) of the cases. Seventy three percent of the cases showed LOH at one or more loci, while 60% showed RER in at least one of the loci studied. RER positive cases showed a trend towards better prognosis when compared to RER negative cases. MSI demonstrated a significant association with concomitant loss of p16 and pRB and was inversely correlated with p53 mutations (p=0.03) suggesting that MSI may provide a p53 independent pathway for esophageal tumorigenesis in RER+ cases. MSI showed a trend towards longer survival and absence of distant organ metastasis (p=0.06). CONCLUSION: The present study demonstrates the putative role of microsatellite instability in esophageal squamous cell carcinoma in Indian population. Instability associated with the repetitive sequences, the revealing marks of loss of DNA replication fidelity may serve as an indicator of predisposition to esophageal cancer.

KEY WORDS: Esophageal Cancer, Microsatellite Instability, .

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on genetic instability.