Molecular characterization of paediatric glioneuronal tumours with neuropil-like islands: a genome-wide copy number analysis

Abstract

Paediatric glioneuronal tumour with neuropil-like islands (GTNI) is a rare neoplasm of neuronal differentiation and diffusely infiltrating astroglial and oligodendrocyte-like components. The 2007 World Health Organization classification of central nervous system tumours considered it as a pattern variation of anaplastic astrocytoma. There are few data on paediatric GTNI probably both for their rarity and variable clinical aggressiveness. We studied by SNP/CGH array four tumour samples of GTNI from two males and two females (one new-born and three children aged from 4 to 8 years), in order to identify any possible common genomic alteration. All patients received chemo- and radiotherapy after their surgical treatment. No genomic instability nor recurrent alterations have been demonstrated in two of our GTNI cases. In the remaining two, we detected a mosaic trisomy 8 (15-20%) in one case, and an amplification at 5q14.1 involving DMGDH (partially), BHMT2 and BHMT genes, with the distal breakpoint falling at 23 Kbp from the 5'UTR of JMY, a p53 cofactor. Although the smallness of the sample impairs any clinical-histological correlation, GTNI appear different at the molecular level, with genomic imbalances playing a possible role in at least part of them. Our work gives an important contribution in knowledge and classification of this family of tumours.

Keywords: Database of Genomic Variants (DGV); Glioneuronal tumour with neuropil-like islands (GTNI); SNP/CGH array; amplification; central nervous tumours (CNS); common genomic alteration; copy number variations (CNVs); mosaicism; paediatric brain tumours; variation of anaplastic astrocytoma.

Figure 1

Preoperative Gd-enhanced T1-weighted MR scans showing GTNI lesions. A: Sagittal emispheric scan of case 1; B: Sagittal cervical spinal scan of patient 2; C: Sagittal dorso-lumbar scan of patient 3; D: Axial emispheric scan of patient 4.

Figure 2

Histopathological features of our GTNI tumors: neurocytic-like cells delimiting islands of fine eosinophilic neurofibrillary matrix (A-D). The arrows indicate the rosette glioneuronal islands.

Figure 3

Human Genome SNP/CGH array hybridization profile of chromosome 5 and 8 for the case 1 (A) and case 4 (B). The size of the amplification is indicated by the blue bars and the red dots represent probes with positive Log₂ fluorescence ratios. Chromosome 5 (A) and 8 (B) view are exhibited on the left-side panels and gene views of the proximal and distal amplification breakpoint regions are shown on the right-side panels (A). In the bottom (B) is showed, in the right-side panel, the mosaic amplification of chromosome 8. The order of sample from left to right is: tumour and blood of patients, father and mother blood. (A) Cases 1 with amplification at 5q14.1 including partially DMGDH, BHMT2 and BHMT genes. This amplification is present in the tumour and blood of proband and in the mother blood. (B) In case 4 the level of mosaicism of the entire chromosome 8 duplication is reflected in reduced log₂ values, along the x-axis compared with normal samples and is present only in the tumour sample. The maternal origin of duplication is indicated from blue line that in the table reveals one of the significant SNPs in which it is confirmed the presence of a supernumerary maternal allele.