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

Abstract

Deletion of the short arm of chromosome 1 is common in oligodendroglial 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 (1 out 21) had biallelic inactivation, i.e., methylation of both DIRAS3 alleles. Furthermore, in oligodendroglioma patients biallelic 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. ' 2008 Wiley-Liss, Inc.Key words: DIRAS3; ARHI; oligodendroglioma; 1p; methylation The DIRAS3 gene at 1p31 encodes a small 26 kDa GTPase with 60% homology to Ras and Rap. 1 Despite its affiliation to the RAS superfamily DIRAS3 exhibits characteristics of a tumor suppressor gene. In breast cancer cell lines the expression of DIRAS3 suppresses clonogenic growth, reduces invasiveness and induces apoptosis. 2 The downstream mechanisms conveying these tumor suppressor functions of DIRAS3 have not yet been fully understood. Inhibition of signalling through RAS/MAPK, PI3K and STAT3 pathways, downregulation of cyclin D1, upregulation of p21(WAF1/CIP1) as well as induction of JNK and caspase-independent, calpain-dependent apoptosis have all been attributed to mediate DIRAS3 downstream signaling effects. [2][3][4][5] DIRAS3 is one of about 40 known imprinted genes within the genome. In human tissues, it is solely expressed from the paternal allele, while the maternal copy is silenced early in embryonal development. 1 The gene comprises 2 exons with the entire 229-base pair coding region located in exon 2. Three potential CpG islands have been attributed to DIRAS3. CpG island I is located about 1 kb upstream of the transcription start site, CpG island II spans both the transcription start site and a portion of exon 1 and CpG island III is located within the protein coding region of exon 2. 6 A study on breast cancer cells suggested CpG island II as the functionally most relevant site for epigenetic inactivation. 7 DIRAS3 maps to 1p31, a chromosomal region that often exhibits loss of heterozygosity in oligodendroglial tumors of the brain. 8 In oligodendrogliomas, determination of the 1p deletion status has attracted particula...

Aplasia Ras Homologous Member I Gene and Development of Glial Tumors

“…These results indicate that LOH may be a primary cause for reducing ARHI gene expression in oligodendrioglial tumors. Our results agree with those in other studies [10,11,14]. …”

“…Reduced expression of ARHI was observed in 70.0–80.0% of breast and ovarian, 84.6% of thyroid, and 42.3% of well-differentiated pancreatic endocrine cancers [10–13]. Lack of expression of ARHI gene is strongly associated with development of oligodendrioglial tumors [14]. …”

“…The maternally-silenced ARHI gene is expressed only from the paternal allele and is constitutively expressed in normal ovary, breast, heart, liver, pancreas, thyroid and brain tissues. Expression is lost or markedly down regulated by LOH or hypermethylation in most cancers of ovary, breast, pancreas, thyroid, and brain [10–14]. …”

MiR-185 Targets the DNA Methyltransferases 1 and Regulates Global DNA Methylation in human glioma

“…Some of the genes, such as events in the MAPK, Wnt, and Jak-STAT signal pathways, were also involved in regulating the development of tumors. In addition, several of the promoter-hypermethylated genes were associated with the development of human cancers and these include GIPC2, DIRAS3, TYSPL6, EDNRB, FYN, GDNF, RASSF1, and RASSF2 [38-43]. Apparently, the research strategies and resulting data are valuable for the evaluation of the significance of DMRs in gliomas.…”

A Systemic Analysis of Transcriptomic and Epigenomic Data To Reveal Regulation Patterns for Complex Disease

“…Additionally, several target genes of these miRNAs have been validated in previous studies, e.g. , RAB18 , RSU1 , GTPBP4 , DIRAS3 , and F3 (Behrends et al 2003; Chunduru et al 2002; Lee et al 2007; Riemenschneider et al 2008; Gessler et al 2010). Taken together, our findings highlight several miRNAs that may regulate multiple signaling cascades crucial for gliomagenesis and therefore, these miRNAs could be therapeutically significant.…”