Copy-Neutral Loss of Heterozygosity at the p53 Locus in Carcinogenesis of Esophageal Squamous Cell Carcinomas Associated with p53 Mutations

Abstract

Purpose: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis.Experimental Design: We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH).Results: In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration.Conclusions: LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation.

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Curcumin Enhances the Efficacy of Chemotherapy by Tailoring p65NFκB-p300 Cross-talk in Favor of p53-p300 in Breast Cancer

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Clinical aspect and molecular mechanism of DNA aneuploidy in gastric cancers

“…Recent analysis showed that LOH without copy number changes at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. This copy-neutral LOH might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutations [87]. Our data suggest that copy-neutral LOH, occurring because of CIN, might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutations.…”