LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

We previously described a cohort of grade II oligodendroglioma (OII) patients,in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at ahigher risk of relapse. In this study, we evaluated the CpG methylation of theputative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoterin the same OII cohort, to investigate whether a correlation could be found betweenEMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-threetumor samples from OII patients were collected over a period of 10 years. Seventeenglioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients.The EMP3, O6-methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2)promoter methylation, evaluated by methylation-specific PCR, and the isocitratedehydrogenase 1 (IDH1) mutation, identified by sequencing, were compared betweenthe OII and GBM histotypes. The EMP3 promoter methylation was correlated withthe analysis of LOH 19q, performed by microsatellite amplification, in OII patients.Disease progression-free interval was evaluated in the OII patients with the EMP3methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 andMGMT promoter methylation was more frequent in OII than in GBM patients, and theIDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes.Both LOH+/- 19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19qand EMP3 gene promoter methylation was observed in the OII patients at a higherrisk of relapse. Our results suggest that a total (cytogenetic and epigenetic)functional loss of both EMP3 alleles accounts for the reduced disease progression-freeinterval in OII patients. Although the small sample size limits the strength ofthis study, our results support testing this hypothesis in larger cohorts of patients,considering the methylation of the EMP3 gene promoter together with LOH 19q asan indication for treatment with adjuvant therapy ab initio in order to improvethe overall survival of OII patients.