Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features

Abstract

BackgroundPilocytic astrocytoma is the most common type of brain tumor in the pediatric population, with a generally favorable prognosis, although recurrences or leptomeningeal dissemination are sometimes also observed. For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features, and the clinical pattern of the disease.MethodsEighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in this study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples).ResultsBioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression.ConclusionsHere we have shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1810-z) contains supplementary material, which is available to authorized users.

Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas

“…In particular, Jeyapalan et al [ 20 ] identified an intergenic CpG site associated to IRX2 that resulted to be differentially methylated between the two tumor groups; whereas we detected a differential methylation of a CpG island that spans the promoter region and part of the gene body of IRX2 . In our sample set, IRX2 gene showed a hypermethylation and an expected downregulation in supratentorial PAs compared to the infratentorial PAs (Figure 4A ), confirming the gene expression profile observed by the other studies [ 16 , 18 , 20 ]. The expression level of this gene was in line with that observed in the normal tissues (Figure 4B and Figure 4C ), suggesting that its downregulation is probably more of a reflection of where the tumor develops rather than the onset of PA per se .…”

“…The differentially expressed genes identified by Sharma and colleagues [ 16 ] are implicated in the development of the forebrain and the hindbrain. One of these genes, IRX2 , was found differentially expressed [ 16 , 18 , 20 ] and differentially methylated between infratentorial and supratentorial PAs in our and other studies [ 5 , 20 ]. In particular, Jeyapalan et al [ 20 ] identified an intergenic CpG site associated to IRX2 that resulted to be differentially methylated between the two tumor groups; whereas we detected a differential methylation of a CpG island that spans the promoter region and part of the gene body of IRX2 .…”

“…Other members of the Iroquois (IRO/IRX) family, IRX1 , IRX3 and IRX5 have been found differentially methylated [ 5 , 20 ] and/or expressed [ 5 , 16 , 18 , 20 ] between supratentorial and infratentorial PAs, suggesting that these genes may have an important role in specific location cancer development.…”

In silico analysis identifies a putative cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma

“…This left eight genes to be analyzed (Ascl1, Irx2, Irx5, Klf15, Meis1, Msx2, Pax3, and Pbx3). In order to validate these genes, an independent dataset of gene expression from pilocytic astrocytoma tumors was interrogated [45]. All eight of these genes were reported to be overexpressed in infratentorial as compared to supratentorial tumors in this independent dataset, validating these findings.…”

A new NFIA:RAF1 fusion activating the MAPK pathway in pilocytic astrocytoma

“…To explore the expression level of RAF1 mRNA in the PA specimen in comparison with other PA expression profiles, we examined two large online available datasets containing HG-U133_Plus_2 expression array data from 47 (E-GEOD-73066) and 49 (E-GEOD-44971) PA patients, respectively (15,16). RAF1 was not differentially expressed (data not shown), indicating that activation of Raf-1, rather than its overexpression, is the cancer driver event in the patient.…”