- Case report
- Open Access
Homozygous deletion of TNFRSF4, TP73, PPAP2B and DPYD at 1p and PDCD5 at 19q identified by multiplex ligation-dependent probe amplification (MLPA) analysis in pediatric anaplastic glioma with questionable oligodendroglial component
© Torres-Martín et al.; licensee BioMed Central Ltd. 2014
Received: 3 October 2013
Accepted: 11 December 2013
Published: 6 January 2014
Pediatric oligodendrogliomas are rare and appear to show a different molecular profile from adult tumors. Some gliomas display allelic losses at 1p/19q in pediatric patients, although less frequently than in adult patients, but this is rare in tumors with an oligodendroglial component. The molecular basis of this genomic abnormality is unknown in pediatric gliomas, but it represents a relatively common finding in pediatric oligodendroglioma-like neoplasms with leptomeningeal dissemination.
Multiplex ligation-dependent probe amplification (MLPA) analysis using SALSA P088-B1 for the analysis of the 1p/19q allelic constitution in a pediatric anaplastic (oligodendro)-glioma showed homozygous co-deletion for markers: TNFRSF4 (located at 1p36.33), TP73 (1p36.32), PPAP2B (1pter-p22.1), DPYD (1p21.3), and PDCD5 (19q13.12), and hemizygous deletion of BAX (19q13.3-q13.4). No sequence changes for R132 and R172 of the IDH1/2 genes were identified.
The molecular findings in this pediatric anaplastic glioma do not allow for a clearly definitive pathological diagnosis. However, the findings provide data on a number of 1p/19q genomic regions that, because of homozygotic deletion, might be the location of genes that are important for the development and clinical evolution of some malignant gliomas in children.
According to Hargrave D high grade gliomas in pediatric oncology generally group grade III and IV tumors with astrocytic or oligodendroglial nature, and include anaplastic astrocytomas (grade III), glioblastomas (grade IV) and anaplastic tumors (grade III) that have a major oligodendroglial component, i.e., pure oligodendrogliomas and mixed oligo-astrocytomas. Although malignant astrocytomas represent approximately 8%-10% of all pediatric CNS tumors, most arising in the supratentorial region, high-grade oligodendrogliomas in children are rare. An incidence of 6% has been reported for oligodendroglial tumors (including pure oligodendrogliomas and mixed oligo-astrocytomas) in children aged 0–14 years. The histology of these neoplasms with oligodendroglial component is classical and has been described as having a “fried-egg” appearance with “chicken-wire” vasculature. Anaplastic variants are primarily based on the presence of mitotic activity, microvascularization and necrosis, while anaplastic astrocytomas are diffusely infiltrating tumors with increased cellularity, distinct nuclear atypia and marked mitotic activity[3, 4]. The molecular biology of adult malignant gliomas is now well defined for tumors with either astrocytic or oligodendroglial characteristics. Both types of gliomas are very complex and genetically heterogeneous, with multiple alterations in critical pathways, primarily alterations of MGMT (methylation), IDH1/2 (mutation), 1p/19q co-deletion, EGFR and PI3K pathway variations, and p53 or Rb pathway mutation[5, 6]. Among the pediatric malignant gliomas, EGFR gene amplification appears to occur less frequently than in tumors from adult patients, and only 2% have the EGFRvIII variant. In contrast, it appears that PDGFRA and PDGFRB are more commonly affected in high-grade pediatric gliomas[1, 7, 8]. Recently, whole genome sequencing in low-grade pediatric gliomas has identified multiple genetic alterations involving several genes such as BRAF, RAF1, FGFR1, MYB and MYBL1[9, 10]. Copy number alteration analysis has demonstrated gains of chromosomes 7, 8 and 5q and loss of 1p. Up to 6 significantly recurrent regions of focal deletion have been identified: 9p21.3 (and the adjacent region), 6q26, 10q21.3, 8p22 and 13q31.3, where multiple genes with functions related to cancer development are located. In this report we describe the partial concurrent homozygous deletion at 1p/19q in an anaplastic glioma (or oligodendroglioma) that took place in a 6-year-old boy. This event might provide insights on a subgroup of pediatric (oligodendro)-gliomas with 1p/19q involvement.
Medical history and examination
A 6-year-old boy was admitted to the La Paz Hospital for complaining of tremors in the left arm. The patient had a history of occasional holocranial headaches and vomiting over the last 2 months and was experiencing thalamic pain. There were no memory or behavioral changes or performance impairment, and the examination revealed no papilloedema. The patient had a postural tremor (6–8 Hz) in the outstretched left arm, which was more prominent in the distal muscle groups. The tremor was slightly accentuated when moving the arm. The tremors ceased when the limb was at rest and when the patient was asleep. The patient had no nystagmus or gait ataxia, and his speech was normal. His osteo-cutaneous reflexes were slightly enhanced on the left side, but he had no sensory abnormalities. The examination revealed a slight left hemiparesis. The patient’s left hand was closed due to dystonia, and his left foot presented dystonia when walking.
The child underwent a right frontal craniotomy, and a trans-cortical frontal approach to the right lateral ventricle was performed for a gross total resection (GTR) of the tumor. This procedure was accomplished using a micro-neurosurgical technique. At the completion of the resection, an endoscopic third ventriculostomy was performed. An intraoperative pathological examination identified an anaplastic (possibly astrocytic) glioma.
The patient’s postoperative recovery was uneventful. There was a dramatic improvement in his symptoms in the immediate postoperative period with virtual cessation of the tremors. The initial follow-up using 3 T-MR images obtained 1 month after the surgery showed a GTR of the tumor and no hydrocephalus. After the initial follow-up, the child was treated with radiotherapy and chemotherapy. An MR image obtained 9 months later revealed no tumor recurrence, and the patient remained neurologically intact (Figure 1B). No changes have been observed after 2 years of follow-up.
The pathology diagnosis was anaplastic glioma, although a 1p/19q analysis was suggested to obtain clues as to the presence of a possible oligodendroglial component. The unconventional microscopic pattern and the infrequent presentation of oligodendrogliomas in pediatric patients[2, 3] could, however, justify our generic diagnosis.
Samples and DNA preparation
Samples and clinical-pathological data were obtained according to the hospital ethics committee procedures. DNA was isolated from frozen tumor and peripheral blood using the Wizard Genomic DNA purification kit (Promega). DNA from an oligodendroglioma with known 1p/19q loss was used as a positive control, and DNA from four healthy volunteers were used as references for multiplex ligation-dependent probe amplification (MLPA) reactions.
Multiplex ligation-dependent probe amplification (MLPA) analysis
Summary of run by Coffalyser
Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutation analysis
The genomic regions spanning the R132 codon of IDH1 and R172 of IDH2 genes were amplified and sequenced with an ABI PRISM 3100 Genetic analyzer and Sequencing Analysis 5.1.1 software (Applied Biosystem, Foster City, CA, USA) using the primers and conditions described previously[14, 15].
Discussion and conclusions
Biological process of altered genes identified by MLPA in pediatric glioma and of neighbour genes located in the critical deleted regions
Inflammatory and immune response
DNA damage response
Calcium ion binding
Blood vessel development
Purine base catabolic process
Early endosome to late endosome transport
Protein complex assembly
Negative regulation of signal transduction
Regulation of humoral immune response
Written informed consent was obtained from the parents for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Also, the molecular studies were performed on anonymized samples provided to the Molecular Neuro-Oncogenetics laboratory (IdiPAZ).
This work is part of a research supported by grant PI10/1972, from Fondo de Investigaciones Sanitarias (FIS), Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.
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