Frameshift mutations at coding mononucleotide repeat microsatellites in endometrial carcinoma with microsatellite instability

BACKGROUND, Microsatellite instability (MI) is a frequent occurrence in end ometrioid carcinoma of the endometrium (EC). Several genes known to contain mononucleotide short tracts in their coding sequences (TGF-beta RII, IGFII R, BAX, hMSH6, and hMSH3) are likely targets for mutations in these tumors. METHODS, DNA from 24 patients with EC and MI was extracted from blood and f rom fresh-frozen and paraffin embedded tumor tissue. Seven of these patient s were found to have metastatic spread to paraaortic lymph nodes. DNA also was studied from 10 patients with EC without MI. RESULTS. Frameshift mutations at coding mononucleotide repeats were detecte d by single strand conformation polymorphism analysis and DNA sequencing. F rameshift mutations were detected more frequently in BAX (11 of 24 MI posit ive (+) tumors; 45.8%) than in TGF-beta RII (0 of 24 tumors; 0%), IGFIIR (3 of 24 tumors; 12.5%), hMSH3 (6 of 24 tumors; 25%), or hMSH6 (0 of 24 tumor s; 0%). The mutations frequently were distributed heterogeneously throughou t the tumors. Overall, frameshift mutations at 1 or more of these mononucle otide repeat microsatellites were found in 17 of 24 MI+ tumors (70.8%) but in none of the 10 MI negative neoplasms. In the seven EC patients with lymp h node metastases, mutations in IGFRII were found more commonly in those wi th metastatic (three of seven patients) rather than primary (one of seven) tumors. CONCLUSIONS. The results of the current study confirm that BAX is an import ant target gene in ECs with MI. The frequent detection of IGFRII frameshift mutations in lymph node metastases suggest that IGFRII may play a role in tumor progression in these patients. Cancer 2000;88:2290-7, (C) 2000 Americ an Cancer Society.