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

Cancer. 2001 Dec 1;92(11):2829-36. doi: 10.1002/1097-0142(20011201)92:11<2829::aid-cncr10094>3.0.co;2-3.


Background: Microsatellite instability (MI) is frequent in endometrial carcinomas (ECs), but its occurrence in ovarian tumors is uncertain. Microsatellite instability positive ECs frequently are associated with frameshift mutations 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 tissue. After preliminary results, the series was expanded by including 41 additional, previously selected, endometrioid and clear cell carcinomas. Microsatellite instability analysis was assessed by evaluating three (CA)n dinucleotide repeats (D2S123, D5S346, D17S250) and two mononucleotide tracts (BAT 25 and BAT 26). Frameshift mutations at coding mononucleotide repeats (IGFIIR, TGF beta II, BAX, hMSH6, and hMSH3) were investigated by single-strand conformation polymorphism analysis and DNA sequencing. MLH-1 methylation was 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 carcinomas with 41 additional endometrioid and clear cell carcinomas, MI was found 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 hypermethylation was identified in three of six MI positive tumors.

Conclusions: Microsatellite instability was infrequent in this series of ovarian 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • Female
  • Frameshift Mutation
  • Humans
  • Microsatellite Repeats / genetics*
  • Multidrug Resistance-Associated Proteins*
  • MutL Protein Homolog 1
  • MutS Homolog 3 Protein
  • Neoplasm Proteins / genetics*
  • Neoplasm Staging
  • Nuclear Proteins
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • bcl-2-Associated X Protein


  • Adaptor Proteins, Signal Transducing
  • BAX protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • MLH1 protein, human
  • MSH3 protein, human
  • Multidrug Resistance-Associated Proteins
  • MutS Homolog 3 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • MutL Protein Homolog 1
  • multidrug resistance-associated protein 1