Molecular pathogenesis of pediatric astrocytic tumors

Abstract

Astrocytomas are the most common pediatric brain tumors, accounting for 7%-8% of all childhood cancers. Relatively few studies have been performed on their molecular properties; therefore, classification of pediatric astrocytic tumors into genetic subtypes similar to that of adult tumors remains to be defined. Here, we report an extensive characterization of 44 pediatric astrocytomas--16 diffuse astrocytomas (WHO grade II), 10 anaplastic astrocytomas (WHO grade III), and 18 glioblastomas (WHO grade IV)--in terms of genetic alterations frequently observed in adult astrocytomas. Some form of p53 mutation was found in three diffuse astrocytomas, in three anaplastic astrocytomas, and in six glioblastomas examined; PTEN mutations were detected only in two glioblastomas. EGFR amplification was detected in only one anaplastic astrocytoma and two glioblastomas, but no amplification was observed for the PDGFR-alpha gene. Loss of heterozygosity (LOH) on 1p/19q and 10p/10q was less common in pediatric astrocytic tumors than in those seen in adults, but the frequency of LOH on 22q was comparable, occurring in 44% of diffuse astrocytomas, 40% of anaplastic astrocytomas, and 61% of glioblastomas. Interestingly, a higher frequency of p53 mutations and LOH on 19q and 22q in tumors from children six or more years of age at diagnosis was found, compared with those from younger children. Our results suggest some differences in children compared to adults in the genetic pathways leading to the formation of de novo astrocytic tumors. In addition, this study suggests potentially distinct developmental pathways in younger versus older children.

Fig. 1

Allelic patterns of chromosomes 1p, 19q, 10p, and 10q in 10 anaplastic astrocytomas and 18 glioblastomas from pediatric patients. A G-banded ideogram of chromosome is shown on the left, and the corresponding polymorphic loci are shown to the right of the ideogram. Case numbers are listed at the top of each column. The CRDs on chromosomes 19q and 10q are indicated by the brackets on the right.

Fig. 2

Analysis of 22q LOH in 16 diffuse astrocytomas, 10 anaplastic astrocytomas, and 18 glioblastomas. Ideogram of chromosome 22 and the location and order of microsatellite markers are on the left; case numbers are listed at the top. Rectangular areas indicate CRDs in the cases of diffuse astrocytoma, in glioblastomas of younger patients, and in glioblastomas of older children.

Fig. 3

GeneScan electrophorogram of several 19q and 22q markers in normal tissue and in glioblastoma. The numbers in the right corner of each panel refer to the ratio of larger to shorter allele. Arrows indicate LOH. Markers are indicated at the bottom of the panels. (A) Glioblastoma case 1 retains heterozygosity for both D19S219 and D19S596, while glioblastoma case 16 shows allelic loss for both D19S219 and D19S596. (B) Glioblastoma case 1 shows LOH for D22S1147 and D22S928 while retaining heterozygosity for D22S1176. For glioblastoma case 17, D22S1176 exhibits allelic loss, whereas D22S1147 and D22S928 exhibit retention of both alleles.