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Loss of Heterozygosity and Internal Tandem Duplication Mutations of the CBP Gene Are Frequent Events in Human Esophageal Squamous Cell Carcinoma

¹Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey;² Laboratory for Cancer Research, Zhengzhou University, Henan, China; and³ Bioscience Division and Center for Human Genome Studies, Los Alamos National Laboratory, Los Alamos, New Mexico

ABSTRACT

Purpose: Cyclic AMP response element binding protein binding protein (CBP), a nuclear transcriptional coactivator protein, is an important component of the cAMP signal transduction pathway. In this study, we systematically analyzed the pattern and frequency of CBP gene alterations in esophageal squamous cell carcinoma (ESCC) samples from Linzhou (Linxian), China.

Experimental Design: Using microsatellite markers D16S475, D16S2622, and D16S523 within the chromosome 16p13.3 locus flanking the CBP gene, we observed loss of heterozygosity (LOH), microsatellite instability (MSI), or homozygous deletion in 16 of 26 ESCC samples. Additional ESCC samples were analyzed using different sets of microsatellite markers (CS1–CS5) within the introns or in close proximity to the 3' end of the CBP gene.

Results: The data showed that CBP gene LOH or MSI occurred in 9 of 19 ESCC samples. A detailed genetic alteration map of the CBP gene showed that an LOH or MSI hot spot occurred within intron 2 of the CBP gene. Furthermore, ESCC samples were investigated for CBP gene mutation by conformation sensitive gel electrophoresis and DNA sequencing. These results revealed that most of the shifted fragments contained internal tandem duplication (ITD), frequently in the regions encoding the histone acetyltransferase domain and COOH-terminal transactivating domain one of the CBP gene. The presence of ITD within the CBP gene was additionally confirmed by Southern blot analysis and sequencing.

Conclusions: These studies show that LOH and ITD of the CBP gene are frequent genetic events in human ESCC. These alterations may have functional importance in the development of human ESCC.

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