Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Deletion of the short arm of chromosome 1 is common in oligoden-droglial tumors and has been identified as a powerful molecular marker for response to radio- and chemotherapy as well as favorable prognosis. Here, we investigated a series of 59 human primary gliomas for aberrations of the DIRAS3 (ARHI) gene, a maternally imprinted RAS-related tumor suppressor at 1p31. We found that DIRAS3 mRNA expression levels were significantly decreased in oligodendrogliomas with 1p deletion when compared to tumors with retention on 1p. While mutational analysis yielded no tumor-associated mutations, assessment of the methylation status of DIRAS3 showed biallelic DIRAS3 inactivation due to methylation of the retained allele in 95% of oligodendrogliomas (19 out of 20) with 1p deletions. In contrast, only 28% of oligodendrogliomas (5 out of 18) without 1p deletions and less than 5% of astrocytic tumors (I out 21) had biallelic inactivation, i.e., methylation of both DIRAS3 alleles. Furthermore, in oligodendroglioma patients bialielic DIRAS3 inactivation was significantly associated with low DIRAS3 transcripts levels and longer overall survival. Taken together, our data suggest DIRAS3 as a novel, prognostically relevant candidate gene that is frequently methylated and silenced in oligodendroglial tumors with 1p deletion. (C) 2008 Wilcy-Liss, hic.