Integrated analysis of mismatch repair system in malignant astrocytomas.
Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1-93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.
Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain ; IBMCC and IBSAL, (USAL/CSIC/University Hospital), Salamanca, Spain.
Irene
I
Rodríguez-Hernández
Juan Luis
JL
Garcia
Angel
A
Santos-Briz
Aurelio
A
Hernández-Laín
Jose María
JM
González-Valero
Juan Antonio
JA
Gómez-Moreta
Oscar
O
Toldos-González
Juan Jesús
JJ
Cruz
Javier
J
Martin-Vallejo
Rogelio
R
González-Sarmiento
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D045643:DNA Repair Enzymes