Molecular and clinicopathological analysis of ovarian carcinomas with and without microsatellite instability.
BACKGROUND
Microsatellite instability (MSI) occurs in sporadic ovarian carcinomas. This study tests the hypothesis that ovarian carcinomas arising through the mutator pathway have distinctive clinical and molecular features that affect clinical outcome.


METHODS
The MSI status was evaluated in 66 ovarian carcinomas and 11 epithelial ovarian tumors of low malignant potential. For the analysis with the microsatellite markers, a fluorescence-based PCR method was employed and the prognostic significance of the MSI status was assessed. DNA copy number changes in tumors with and without MSI were analyzed by comparative genomic hybridization.


RESULTS
High-frequency MSI (MSI-H) was found in 30% of the carcinomas, whereas low-frequency MSI (MSI-L) occurred in 32%. In LMP tumors, only MSI-L was detected (18%). There was a trend for tumors with MSI-H and MSI-L to have a poor prognosis, but this relationship did not reach significance (p=0.09 and p=0.07, respectively). MSI-H in carcinomas was significantly associated with poor differentiation (p=0.03) and higher clinical stage (p=0.03). No correlation was found between different histological types of ovarian carcinoma and the microsatellite status. In a multivariate analysis, MSI at the dinucleotide repeat D5S346 was found to be of independent prognostic significance (p<0.008) for disease-specific survival. There was no association between the total number of genetic aberrations per tumor and the MSI status.


CONCLUSIONS
Microsatellite instability is a relatively common event in ovarian carcinoma. The data indicate that instability of a single microsatellite marker on chromosome 5 (D5S346) might be indicative of disease progression when detected in early clinical stages.
Dellas
Athanassios
A
Department of Gynecology, University of Basel, Obere, Batterieweg 39, CH-4059 Basel, Switzerland. a.dellas@unibas.ch
Puhl
Alex
A
Schraml
Peter
P
Thomke
Sabine E
SE
Rüschoff
Josef
J
Mihatsch
Michael J
MJ
Moch
Holger
H
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D018628:Gene Dosage; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D009693:Nucleic Acid Hybridization; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D015996:Survival Rate
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein