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

Idoya Zazpe-Cenoz, Department of Neurosurgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain ; Noemi Perez-Janices, Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain ; Idoia Blanco-Luquin, Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain ; Edurne Barba- Ramos, Department of Pathology Section A, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain ; Berta Ibáñez, 4Red de Evaluación en Servicios Sanitarios y Enfermedades Crónicas (REDISSEC), Navarra, Spain ; David Escors, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain ; David Guerrero-Setas, Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet, Navarra, Spain


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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