Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors

BACKGROUND. Microsatellite instability (MI) is frequent in endometrial carc inomas (ECs), but its occurrence in ovarian tumors is uncertain. Microsatel lite instability positive ECs frequently are associated with frameshift mut ations in coding mononucleotide tracts in IGFIIR, BAX, hMSH6, and hMSH3. METHODS. DNA from 52 consecutive patients with ovarian tumors (10 benign, 7 borderline, and 35 malignant) was obtained from neoplastic and normal tiss ue. After preliminary results, the series was expanded by including 41 addi tional, previously selected, endometrioid and clear cell carcinomas. Micros atellite instability analysis was assessed by evaluating three (CA)n dinucl eotide repeats (D2S123, D5S346, D17S250) and two mononucleotide tracts (BAT 25 and BAT 26). Frameshift mutations at coding mononucleotide repeats (IGF IIR, TGF beta II, BAX, hMSH6, and hMSH3) were investigated by single-strand conformation polymorphism analysis and DNA sequencing. MLH-1 methylation w as assessed by methylation specific PCR. RESULTS. Microsatellite instability was identified in only 2 of the 52 (3.8 %) tumors of the initial series (1 endometrioid and 1 clear cell carcinoma) . After expanding the initial series of 15 endometrioid and clear cell carc inomas with 41 additional endometrioid and clear cell carcinomas, MI was fo und in 7 of the total series of 56 endometrioid and clear cell carcinomas ( 12.5%). Frameshift mutations in coding mononucleotide tracts were detected in BAX (6 of 7), IGFIIR (1 of 7), and MSH3 (2 of 7). MLH-1 promoter hyperme thylation was identified in three of six MI positive tumors. CONCLUSIONS. Microsatellite instability was infrequent in this series of ov arian tumors, and it was limited to endometrioid and clear cell carcinomas. Like EC, many ovarian carcinomas with MI follow the same process of MLH-1 promoter methylation and accumulation of mutations in coding mononucleotide tracts. Cancer 2001;92:2829-36. (C) 2001 American Cancer Society.