Integrated Analysis of Mismatch Repair System in Malignant Astrocytomas

• Published in: PloS one Vol. 8; no. 9; p. e76401
• Main Authors: Rodríguez-Hernández, Irene, Garcia, Juan Luis, Santos-Briz, Angel, Hernández-Laín, Aurelio, González-Valero, Jose María, Gómez-Moreta, Juan Antonio, Toldos-González, Oscar, Cruz, Juan Jesús, Martin-Vallejo, Javier, González-Sarmiento, Rogelio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.09.2013; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Analysis; Astrocytoma; Astrocytoma - genetics; Astrocytoma - metabolism; Astrocytoma - mortality; Astrocytoma - pathology; Astrocytomas; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain; Brain cancer; Brain tumors; Cancer therapies; Chemotherapy; Cohort Studies; Defects; Deoxyribonucleic acid; DNA; DNA Methylation; DNA Mismatch Repair - genetics; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Female; Gene mutation; Gene polymorphism; Genes; Genetic aspects; Genetic recombination; Genomes; Genomics; Glioblastoma; Hospitals; Humans; Immunoenzyme Techniques; Male; Medical prognosis; Medicine; Methylation; Microsatellite Instability; Middle Aged; Mismatch repair; MLH1 protein; MMR protein; MSH2 protein; MSH6 protein; Mutation; Mutation - genetics; Neoplasm Grading; Neurosurgery; Oncology; Pathogenesis; Pathology; Patients; Pediatrics; Polymorphism; Prognosis; Promoter Regions, Genetic - genetics; Proteins; Radiation therapy; Repair; Stability; Studies; Survival; Survival Rate; Tissue Array Analysis; Tumors; Yeast; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076401

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.