Balkan Journal of Medical Genetics

APLASIA RAS HOMOLOGOUS MEMBER I GENE AND DEVELOPMENT OF GLIAL TUMORS
Yakut S1, Tuncer MR2,* Berker M3, Goksu E2, Gurer I4, Ozes ON1, Luleci G1, Karauzum SB1
*Corresponding Author: Sibel Berker Karauzum, Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University Antalya, Turkey; Tel.: +90 242 2496971; Fax: +90 242 2274482; E-mail: sibelkarauzum@akdeniz.edu.tr
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DISCUSSION

The ARHI gene, localized at 1p31 and maternally imprinted, was studied in several tumor types and was found to have expression alterations [13]. 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]. Our results demonstrated reduction of ARHI expression in seven of 21 glial tumors (33.3%). Since LOH of the functional paternal allele is considered one of the mechanisms that lead to decreased ARHI expression [13], we performed LOH analysis in 21 glial tumors and found LOH in two of 21 (9.5%) samples. Although the number of cases were insufficient, the cases with LOH were all oligodendroglial tumors. Five oligodendroglial tumors were included in this study and two with LOH of five oligodendroglial tumors also showed decreased ARHI expression in real time RT-PCR. That is why the frequency (40.0%) is so important. These results indicate that the area of normal allele II 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]. In addition to LOH, expression of ARHI from the paternal allele can also be down-regulated by hypermethylation [17]. In previous studies, hypermethylations of ARHI CpG island I, II and III, were observed in 35.0% of breast cancer and in 95.0% of oligodendrioglial tumors associated with 1p deletion [9,14]. We observed hypermethylation in only two of the 21 glial tumor samples (9.5%). One of these was oligodendrioglial, and the other one was AA. The mRNA level of ARHI in oligodendrioglial tumor with LOH on 1p was significantly lower than that of astrocytoma without LOH on 1p. This result indicates that there could be an association between ARHI transcriptional repression and allelic LOH profile on 1p. Although hypermethylation of CpG island II was associated with complete loss of ARHI expression in breast cancer [9], we found only hypermethylation of CpG island I in glial tumors. Our result is in line with a previously published study [14]. Thus, it seems that hypermethylation of CpG island I can also be responsible for down-regulation of ARHI expression. We also found increased ARHI expression in 14 glial tumors, 10 of which were GBM tumors but have no explanations for the mechanism behind this. We speculate that increased levels of growth factors (EGF, PDGF), their receptors (EGFR, PDGFRA) in tumor microenvironment or constituve activation of PI3K, MAPK, STAT3 pathways may be responsible for our results [14]. We conclude that decreased ARHI expression may play a role in development of glial brain tumors. However, LOH and methylation analysis need to be evaluated in larger number of samples before ARHI can be considered to be a prognostic marker in glial tumors.

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