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Human pathology

Frameshift mutations of tumor suppressor gene EP300 in gastric and colorectal cancers with high microsatellite instability.


PMID 23759652

Abstract

Several lines of evidence show that chromatin remodeling is involved in the pathogenesis of disease, including cancer. The E1A-binding protein p300 functions as a histone acetyltransferase and is considered an important modulator of chromatin remodeling. The aim of this study was to explore whether E1A-binding protein p300 is somatically mutated and expressionally altered in gastric and colorectal cancers. By analyzing a public database, we found that E1A-binding protein p300 had mononucleotide repeats in exons 27 and 31 that could be mutation targets in cancers with microsatellite instability. We analyzed mutations in the mononucleotide repeats in 91 gastric and 101 colorectal cancers with high microsatellite instability or stable microsatellite instability by single-strand conformation polymorphism analysis and DNA sequencing. We also analyzed E1A-binding protein p300 expression in gastric and colorectal cancers by immunohistochemistry staining. We found E1A-binding protein p300 frameshift mutations (4 in exon 27 and 3 in exon 31) in 3 gastric and 4 colorectal cancers that were detected exclusively in cancers with high microsatellite instability (7/80). In the immunohistochemistry study, loss of E1A-binding protein p300 expression was identified in 12% and 24% of the gastric and colorectal cancers, respectively, irrespective of microsatellite instability status. Loss was more common in tumors with E1A-binding protein p300 frameshift mutations. Frameshift mutations of E1A-binding protein p300 and its expressional loss may be a feature of gastric and colorectal cancers with high microsatellite instability. These alterations could contribute to cancer pathogenesis by deregulating E1A-binding protein p300-mediated functions.