Differences Between Pediatric and Adult Malignant Astrocytomas
A number of other molecular analyses have been performed that demonstrate interesting variations between different malignant gliomas in adult and pediatric patients. For example, microsatellite instability, which is common in adult malignant gliomas, was rarely identified in pediatric HGG. The p16INK4a protein (which regulates the Rb protein and cell proliferation) via the (Rb)/p16INK4a/CDK4 pathway was evaluated in 29 pediatric and 107 adult high-grade astrocytomas and demonstrated homozygous deletions for exon 1α and exon 1β in three of 29 (10%) pediatric cases (two grade 3 and one grade 4), 25 of 107 (23%) adult cases (six grade 3 and 19 grade 4), and eight of nine (89%) glioma cell lines. Loss of pRb is rare in pediatric malignant gliomas. Diffuse intrinsic pontine gliomas have recently been shown to express a high rate of PI3K activating mutations, similar to that observed in other pediatric and adult HGGs. HIF2α overexpression has also been linked to pediatric malignant gliomas, a pathway that interacts with EGFR signaling and may account for some of the differences observed with respect to EGFR mutation in this population.
In spite of the malignant nature of HGGs, chromosomal analyses have shown that large deletions, amplifications and translocations are absent from the majority of pediatric samples and suggest that genomic instability is not the primary driving force. High-resolution 244K oligonucleotide array comparative genomic hybridization from 38 pediatric HGG and diffuse intrinsic pontine glioma demonstrated patterns of gains and losses that were distinct from those seen in HGG arising in adults. In particular, 1q gain was identified in 27% of a cohort compared with 9% reported in adults while 13% had no large-scale copy number alterations. Homozygous loss at 8p12 was seen in six of 38 (16%) cases and was confirmed by quantitative real-time PCR (qPCR). Amplification of PDGFRA and MYCN were also observed. Pediatric and adult glioblastomas can also be distinguished by frequent gain of chromosome 1q (30 vs 9%, respectively), lower frequency of chromosome 7 gain (13 vs 74%, respectively) and 10q loss (35 vs 80%, respectively). A genome-wide analysis of DNA copy number aberrations in 33 astrocytic tumors (grade 1–4) demonstrated ≥ten amplifications in the grade 3 and 4 astrocytomas in MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13) and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26) and TP53 (17p3.1) were evident in the grade 2–4 tumors. Five out of seven samples with BRAF mutations had concomitant homozygous deletion of CDKN2A. Abnormal Myb expression may also be associated with pediatric low-grade gliomas.
Of further interest, recent work has shown a family of alterations in histone 3 protein, which has been implicated in the possible epigenetic regulation of DNA. The mutations observed were largely confined to pediatric malignant gliomas, both supratentorial GBM and pontine gliomas, and not found in most adult GBMs. The clinical significance of these mutations will require further study to completely elucidate but further support the unique biology of pediatric malignant gliomas compared with similar lesions in adults.
Microsatellites, PI3K, HIF2α & Chromosomal Analysis
A number of other molecular analyses have been performed that demonstrate interesting variations between different malignant gliomas in adult and pediatric patients. For example, microsatellite instability, which is common in adult malignant gliomas, was rarely identified in pediatric HGG. The p16INK4a protein (which regulates the Rb protein and cell proliferation) via the (Rb)/p16INK4a/CDK4 pathway was evaluated in 29 pediatric and 107 adult high-grade astrocytomas and demonstrated homozygous deletions for exon 1α and exon 1β in three of 29 (10%) pediatric cases (two grade 3 and one grade 4), 25 of 107 (23%) adult cases (six grade 3 and 19 grade 4), and eight of nine (89%) glioma cell lines. Loss of pRb is rare in pediatric malignant gliomas. Diffuse intrinsic pontine gliomas have recently been shown to express a high rate of PI3K activating mutations, similar to that observed in other pediatric and adult HGGs. HIF2α overexpression has also been linked to pediatric malignant gliomas, a pathway that interacts with EGFR signaling and may account for some of the differences observed with respect to EGFR mutation in this population.
In spite of the malignant nature of HGGs, chromosomal analyses have shown that large deletions, amplifications and translocations are absent from the majority of pediatric samples and suggest that genomic instability is not the primary driving force. High-resolution 244K oligonucleotide array comparative genomic hybridization from 38 pediatric HGG and diffuse intrinsic pontine glioma demonstrated patterns of gains and losses that were distinct from those seen in HGG arising in adults. In particular, 1q gain was identified in 27% of a cohort compared with 9% reported in adults while 13% had no large-scale copy number alterations. Homozygous loss at 8p12 was seen in six of 38 (16%) cases and was confirmed by quantitative real-time PCR (qPCR). Amplification of PDGFRA and MYCN were also observed. Pediatric and adult glioblastomas can also be distinguished by frequent gain of chromosome 1q (30 vs 9%, respectively), lower frequency of chromosome 7 gain (13 vs 74%, respectively) and 10q loss (35 vs 80%, respectively). A genome-wide analysis of DNA copy number aberrations in 33 astrocytic tumors (grade 1–4) demonstrated ≥ten amplifications in the grade 3 and 4 astrocytomas in MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13) and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26) and TP53 (17p3.1) were evident in the grade 2–4 tumors. Five out of seven samples with BRAF mutations had concomitant homozygous deletion of CDKN2A. Abnormal Myb expression may also be associated with pediatric low-grade gliomas.
Of further interest, recent work has shown a family of alterations in histone 3 protein, which has been implicated in the possible epigenetic regulation of DNA. The mutations observed were largely confined to pediatric malignant gliomas, both supratentorial GBM and pontine gliomas, and not found in most adult GBMs. The clinical significance of these mutations will require further study to completely elucidate but further support the unique biology of pediatric malignant gliomas compared with similar lesions in adults.
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