Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer.
The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.
Codegoni
A M
AM
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Bertoni
F
F
Colella
G
G
Caspani
G
G
Grassi
L
L
D'Incalci
M
M
Broggini
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D018816:Genes, cdc; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured