Abstract
BackgroundPleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients.MethodsUsing a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences.ResultsIncreasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis.ConclusionsEven taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation.
Highlights
We observed a set of DNA hypermethylation events in anaplastic Pleomorphic xanthoastrocytoma (PXA), its corresponding precursor grade II tumor, overlapping with DNA methylation alterations found in GBM (Figure 3)
We cannot rule out that the epigenetic alterations observed could be attributable to individual-specific DNA methylation phenomena; methylation of these genes has been found in GBM in larger population studies [29,35,36,37,42], indicating that they are most probably involved in the pathogenesis and malignant progression of astrocytic tumors
A recent report analyzing the methylation status of MGMT in 11 grade II PXA concluded that this event was infrequent in PXA [28]. Albeit this finding needs to be assessed in larger population studies, the extensive promoter hypermethylation we found in the anaplastic PXA patient supported the indication of chemotherapy with temozolomide in a similar pattern as it is in other malignant tumors of astrocytic lineage [40]
Summary
Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. They are usually hemispheric, and often they affect children and young adults (median age 26 years) with a frequent history of chronic epilepsy at presentation [1,2,3]. PXA shows a pleomorphic appearance, an intense reticulin network and lipid deposits within ovoid and spindled tumor cells. Eosinophilic granular bodies and lymphocytic infiltrates are observed. The mitotic activity is absent or very low and MIB-1 labeling index is frequently
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