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EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas

2015; Impact Journals LLC; Volume: 6; Issue: 1 Linguagem: Inglês

10.18632/oncotarget.2745

1949-2553

Noemí Pérez‐Janices, Idoia Blanco‐Luquin, Maria Teresa Tuñón, Edurne Barba‐Ramos, Berta Ibáñez, Idoya Zazpe-Cenoz, Maria Teresa Martinez-Aguillo, Berta Hernández, Enrique Martínez-López, Agustín F. Fernández, María Mercado, T. Cabada, David Escors, Diego Megı́as, David Guerrero‐Setas,

Ubiquitin and proteasome pathways

// Noemi Perez-Janices 1 , Idoia Blanco-Luquin 1 , Maria Teresa Tuñón 2 , Edurne Barba-Ramos 2 , Berta Ibáñez 3, 4 , Idoya Zazpe-Cenoz 5 , Maria Teresa Martinez-Aguillo 6 , Berta Hernandez 6 , Enrique Martínez-Lopez 7 , Agustin F. Fernández 8 , Maria Roasario Mercado 2 , Teresa Cabada 9 , David Escors 3 , Diego Megias 10 , David Guerrero-Setas 1 1 Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain 2 Department of Pathology Section A, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain 3 Navarrabiomed-Fundación Miguel Servet, Navarra, Spain 4 Red de Evaluación en Servicios Sanitarios y Enfermedades Crónicas (REDISSEC), Navarra, Spain 5 Department of Neurosurgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain 6 Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain 7 Department of Radiation Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain 8 Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Asturias, Spain 9 Department of Radiology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain 10 Confocal Microscopy Core Unit, Spanish National Cancer Research Centre, Madrid, Spain Correspondence to: D. Guerrero-Setas, e-mail: dguerres@navarra.es Keywords: Brain tumors, EPB41L3, DNA methylation, prognosis, RASSF2, TSP-1 Received: August 05, 2014 Accepted: November 12, 2014 Published: January 24, 2015 ABSTRACT Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3 , RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients’ clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1 ) and bisulfite-sequencing (for RASSF2 ). EPB41L3 , RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2′-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3 , RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse ( p = 0.047) and better ( p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas ( p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance.