Research Papers:

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

Noemi Perez-Janices _, Idoia Blanco-Luquin, Maria Teresa Tuñón, Edurne Barba-Ramos, Berta Ibáñez, Idoya Zazpe-Cenoz, Maria Teresa Martinez-Aguillo, Berta Hernandez, Enrique Martínez-Lopez, Agustin F. Fernández, Maria Roasario Mercado, Teresa Cabada, David Escors, Diego Megias and David Guerrero-Setas

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Oncotarget. 2015; 6:368-380. https://doi.org/10.18632/oncotarget.2745

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Noemi Perez-Janices1, Idoia Blanco-Luquin1, Maria Teresa Tuñón2, Edurne Barba-Ramos2, Berta Ibáñez3,4, Idoya Zazpe-Cenoz5, Maria Teresa Martinez-Aguillo6, Berta Hernandez6, Enrique Martínez-Lopez7, Agustin F. Fernández8, Maria Roasario Mercado2, Teresa Cabada9, David Escors3, Diego Megias10, David Guerrero-Setas1

1Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain

2Department of Pathology Section A, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain

3Navarrabiomed-Fundación Miguel Servet, Navarra, Spain

4Red de Evaluación en Servicios Sanitarios y Enfermedades Crónicas (REDISSEC), Navarra, Spain

5Department of Neurosurgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain

6Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain

7Department of Radiation Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain

8Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), HUCA, Universidad de Oviedo, Asturias, Spain

9Department of Radiology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain

10Confocal Microscopy Core Unit, Spanish National Cancer Research Centre, Madrid, Spain

Correspondence to:

D. Guerrero-Setas, e-mail: [email protected]

Keywords: Brain tumors, EPB41L3, DNA methylation, prognosis, RASSF2, TSP-1

Received: August 05, 2014     Accepted: November 12, 2014     Published: January 24, 2015


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.

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