HUMAN THYMINE-DNA GLYCOSYLASE MAPS AT CHROMOSOME 12Q22-Q24.1 - A REGION OF HIGH LOSS OF HETEROZYGOSITY IN GASTRIC-CANCER

Spontaneous hydrolytic deamination of 5-methylcytosine leads to T:G mi smatches in double-stranded DNA and comprises a major threat for the i ntegrity of both the DNA primary sequence as well as the epigenetic in formation stored in the DNA methylation pattern, Failure of the cellul ar DNA repair machinery to recognize and repair such mismatched nucleo tides can lead to a mutator phenotype and subsequent carcinogenesis, A thymine-DNA glycosylase (TDG) has been described that initiates T:G m ismatch repair by specifically excising the mismatched T, We have stud ied the TDG genomic locus and the expression of this enzyme to evaluat e its role in cancer development, TDG is highly expressed in thymus an d is expressed at lower levels in all human tissues analyzed, The TDG gene has 10 exons covering a region of >25 kb and is located on chromo some 12q22-q24.1. Because gastric tumors have been shown to contain a high percentage of C-->T mutations at CpG sites, we used a microsatell ite found in intron 8 of the TDG locus to screen gastric tumor samples for loss of heterozygosity, Although our analysis showed loss of hete rozygosity in 10 of 24 samples (42%), none of those tumor samples reve aled a mutation in the coding sequence of the remaining TDG allele as analyzed by single-strand conformational polymorphism, Expression of t he TDG was not determined because of the limited availability of RNA i n these primary tumor samples, At present, we have found no evidence t hat TDG is central to the development of gastric cancer, limiting the importance of TDG in T:G mismatch repair and subsequent carcinogenesis .