RESUMEN
BACKGROUND: The correlation between tumor microsatellite instability (MSI) and the accumulation of mutations in KRAS2 and TP53 is uncertain. The authors evaluated the TP53 and KRAS2 genes for mutations in sporadic endometrial carcinomas with microsatellite instability (MSI) and matched MSI negative controls to determine whether defective DNA mismatch repair impacts the patterns of mutations in two genes known to be involved in endometrial tumorigenesis. METHODS: Twenty-five MSI positive endometrial tumors were matched for prognostic factors with 25 MSI negative tumors. Mutations in codon 12 and 13 of KRAS2 were assessed using a polymerase chain reaction (PCR) restriction assay. Mutations in codon 61 of KRAS2 and exons 5-8 of TP53 were evaluated using PCR amplification and single strand conformation variant (SSCV) analysis. All variants were subjected to direct DNA sequencing. RESULTS: KRAS2 and TP53 mutations were identified with equal frequency in the MSI positive and MSI negative groups. For TP53, the authors identified 5 mutations (20%) in the MSI positive specimens compared with 8 (32%) in the MSI negative group. For KRAS2, there were identified 8 mutations (32%) in the MSI positive specimens compared with 7 (28%) in the MSI negative tumors. The mutational spectra evident from sequence analysis of TP53 and KRAS2 variants were similar between MSI negative and MSI positive tumors. MSI negative tumors were more likely to have mutations in both KRAS2 and TP53 than MSI positive tumors, which were rarely mutant in both genes (P=0.046). CONCLUSIONS: Although the overall frequency of mutations in TP53 and KRAS2 is similar, MSI positive tumors are less likely to have mutations in both genes than MSI negative sporadic endometrial carcinomas. MSI positive and MSI negative endometrial carcinomas may arise through distinct genetic pathways.
Asunto(s)
Neoplasias Endometriales/genética , Genes p53/genética , Repeticiones de Microsatélite/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Reparación del ADN , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Reacción en Cadena de la Polimerasa , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Proteínas rasRESUMEN
Frequent loss of chromosome 10q sequences in endometrial cancers suggests the involvement of a tumor suppressor gene. Previous loss-of-heterozygosity (LOH)studies have pointed to the 10q25-q26 region as the likely site of a tumor suppressor involved in endometrial tumorigenesis (S. L. Peiffer et al., 1995, Cancer Res. 55: 1922-1926; S. Nagase et al., 1996, Br. J. Cancer 74: 1979-1983; S. Nagase et al.,1997, Cancer Res. 57: 1630-1633). In an attempt to define further the localization of a tumor suppressor gene at 10q25, we screened a panel of 123 endometrioid adenocarcinomas for loss of heterozygosity of 10q25.3 sequences. Forty-three (35%) revealed LOH at one or more loci. The observed patterns of allelic loss define a minimum consensus region of deletion between D10S221 and D10S610. A sequence-ready bacterial clone contig and a long-range restriction map for a 1-Mb interval spanning the deletion region were developed as the first step in experiments directed toward the discovery the 10q25 tumor suppressor.
Asunto(s)
Carcinoma Endometrioide/genética , Mapeo Cromosómico , Cromosomas Humanos Par 10/genética , Genes Supresores de Tumor/genética , Mapeo Cromosómico/métodos , Cromosomas Artificiales de Levadura/genética , Cromosomas Bacterianos/genética , Clonación Molecular , Femenino , Marcadores Genéticos/genética , Humanos , Pérdida de Heterocigocidad/genética , Mapeo Restrictivo , Eliminación de Secuencia/genéticaRESUMEN
OBJECTIVE: The aim of this study was to assess the involvement of PTEN and other putative 10q tumor suppressors in endometrioid-type adenocarcinomas characterized by loss of 10q sequences. METHODS: PCR-based single-stranded conformational variant analysis and sequencing of individual PTEN exons in 34 tumor specimens and their corresponding normal DNA were used. RESULTS: Thirteen of the 34 tumors (38%) revealed a PTEN mutation: 2 frameshift, 3 nonsense, 3 missense, 3 splice site alterations, and 2 homozygous deletions. CONCLUSION: The observation that greater than 60% of endometrial cancers with 10q LOH lack PTEN mutations, in addition to previously reported LOH data, provides evidence for the existence of other tumor suppressors on 10q. Consideration of PTEN mutation status may prove important in deletion mapping studies to locate additional tumor suppressors on the long arm of chromosome 10.
