BAX SOMATIC FRAMESHIFT MUTATIONS IN ENDOMETRIOID ADENOCARCINOMAS OF THE ENDOMETRIUM - EVIDENCE FOR A TUMOR PROGRESSION ROLE IN ENDOMETRIAL CARCINOMAS WITH MICROSATELLITE INSTABILITY

Microsatellite instability (MI) has been observed in endometrioid aden ocarcinomas of the endometrium, either arising sporadically or in asso ciation with the hereditary colon cancer syndrome. Genes known to cont ain mononucleotide short tracts in their coding sequence are regarded as targets for mutations in these tumors. BAX is a proapoptotic gene t hat contains a tract of eight consecutive deoxyguanosines in its third coding exon. DNA of 26 patients with endometrial carcinoma was extrac ted from blood and from fresh-frozen and paraffin-embedded tumor tissu e. For Mt analysis, microsatellite loci on chromosomes 3, 5, 10, 12, a nd 18 were amplified by PCR. Frameshift mutations in the (G)(8) tract of BAX were detected by single-strand conformation polymorphism (SSCP) analysis. MI at three or more loci was detected in 13 cases. BAX fram eshift mutations were detected in seven Ml(+) tumors (53.8%), but in n one of the 13 Ml(-) neoplasms. In two cases, identical BAX frameshift mutations were detected in different areas of the neoplasm, whereas in the other five cases, BAX mutations were heterogeneously distributed throughout the tumor. Immunostaining with antibodies against the carbo xy terminus of BAX protein was Very useful in assessing the heterogene ous distribution of BAX frameshift mutations in the neoplasms. The res ults suggest that BAX frameshift mutations are frequent in endometrial carcinomas with MI, probably playing a role in the process of tumor p rogression of these neoplasms.