Gastric Cancer 12q22-q24.1: A Region of High Loss of Heterozygosity in Human Thymine-DNA Glycosylase Maps at Chromosome

Spontaneous hydrolytic deamination of 5-methylcytosine leads to T:G mismatches in double-stranded DNA and comprises a major threat for the integrity of both the DNA primary sequence as well as the epigenetic information stored in the DNA methylation pattern. Failure ofthe cellular DNA repair machinery to recognize and repair such mismatched nude otides can lead to a mutator phenotype and subsequent carcinogenesis. A thymine-DNA glycosylase (TDG) has been described that initiates T:G mismatch repair by specifically excising the mismatched T. We have studied the TDG genomic locus and the expression of this enzyme to evaluate its role in cancer development. TDG is highly expressed in thymus and Isexpressed at lower levels in all human tissues analyzed. The rrx; genehas10exonscoveringa regionof >25kb andis locatedon chromosome 12q22-q24.1. Because gastric tumors have been shown to contain a high percentage of C—sT mutations at CpG sites, we used a microsatellite found in intron 8 of the TOG locus to screen gastric tumor samples for loss of heterozygosity. Although our analysis showed loss of heterozygosity in 10 of 24 samples (42%), none of those tumor samples revealed a mutation in the coding sequence of the remaining TDG allele as analyzed by single-strand conformatlonal polymorphism. Expression of the TDG was not determined because ofthe limited availability of RNA in these primary tumor samples. At present, we have found no evidence that TDG is central to the development of gastric cancer, limiting the impor tance of TDG in T:G mismatch repair and subsequent carcinogenesis.