Epigenetic inactivation of the hMLH1 gene in progression of gliomas.
Gliomas (GLs) are characterized by highly variable biologic behavior. After surgical resection and postoperative therapy, they frequently recur with the same or higher-grade histology. Although a number of genetic aberrations have been described in different histologic types of GLs, the molecular mechanisms of histologic and clinical progression are poorly understood. In this study, we have performed longitudinal mismatch repair gene polymerase chain reaction-single strand conformation polymorphism and methylation analysis in paired samples of primary and recurrent GLs to reveal whether the inactivation of the normal DNA repair mechanism is associated with tumor progression. Polymerase chain reaction-single strand conformation polymorphism analysis of the hMLH1 gene was performed in 24 cases, in each case the samples of the first and second biopsies being evaluated simultaneously, but no alterations in the hMLH1 gene were found. Methylation analysis of the CpG sites in the hMLH1 promoter revealed a total of 4 (16.6%) hypermethylations in recurrent GLs. These results suggest that hMLH1 promoter hypermethylation may occur in low-grade GLs, associated with the development and progression of moderate malignant GL, but not with structural alterations in the hMLH1 gene. It seems that hMLH1 promoter hypermethylation is an early event in the development and progression or the clonal evolution of GLs, this gene inactivation proving stable even on tumor recurrence.
Gömöri
Eva
E
Departments of Pathology, Faculty of Medicine, Pécs University, H-7624 Pécs, Szigeti út 12, Hungary. geva@pathology.pote.hu
Pál
József
J
Mészáros
István
I
Dóczi
Tamás
T
Matolcsy
András
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002648:Child; D003131:Combined Modality Therapy; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015996:Survival Rate
D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1