(CA)n simple repeats in DNA were examined at 17 loci in 18 human squamous cell carcinomas of the esophagus and compared with those in normal esophageal tissue from the same patients. Six loci were examined in 32 esophageal papillomas that had been induced by N-nitrosomethylbenzylamine in BD VI rats. Length-altered CA repeats were found in two human tumors and four rat papillomas. Loss of heterozygosity was observed in three human tumors; two rat papillomas had lost microsatellite bands that are common in inbred BD VI rats. Both (CA)n microsatellite length alteration and loss of heterozygosity were clustered at certain loci in the human tumor samples and in the chemically induced rat esophageal tumors. Our findings indicate that genomic instability that results in alteration of repeated sequences not only occurs in human tumors but may also be a consequence of chemical carcinogenesis in rodents.
We have investigated frameshift mutations in exonic repeats in the ATR, BRCA1, BRCA2, PTCH, CTCF, Cx26, NuMa and TGFbetaRII genes, using human tumor samples from stomach, esophagus, breast and skin and melanoma, as well as colon cancer and endometrial cancer cell lines (125 samples in total). We developed a sensitive method to detect mutations in the repeats, using the introduction of an artificial restriction site into a repeat. The method detects a single mutant among 10(3) normal genes. Thus, an alteration in a repeated sequence can be detected unambiguously. The (A)(8) repeat of BRCA2 was found mutated in only two of five colon cell lines with microsatellite instability (MI(+)). The ATR gene has an (A)(10) repeat which was altered in two of three MI(+) stomach cancer samples and one of three MI(+) endometrial cell lines. The TGFbetaRII gene [with an (A)(10) repeat] had the maximal frequency of mutations: 10 out of 13 MI(+) samples. At least one sample from all types of cancers, except melanomas, was positive for TGFbetaRII gene mutations. No mutations were found in repeats in the BRCA1, PTCH, CTCF, NuMA and Cx26 genes in any types of tumors examined. In conclusion, our study indicates that repeats were altered only in MI(+) cells and that the mutation frequencies in the genes studied differ among tumor types. Based on these results, we discuss meaningful and meaningless alterations in exonic repeats.
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