diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of pediatric malignancies and one for which no effective therapy exists.

A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumors in children are identical to cerebral high-grade gliomas of adults.

Cytogenetics

Analysis of DIPG copy number alterations showed recurrent changes distinct from those of pediatric supratentorial high-grade astrocytomas.

Thirty-six percent of DIPGs had gains in platelet-derived growth factor receptor alpha (PDGFRA; 4 to 18 copies) and all showed PDGFR-alpha expression. (#20142589#)

Low-level gains in poly (ADP-ribose) polymerase-1 (PARP1) were identified in some cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways. (#20142589#)

There are involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically based, therapeutic targets directed specifically at this devastating disease. (#20142589#)

CGH gains

 1q : 34%
 Xq : 25%
 2p : 22%
 7p : 22%

CGH losses

 14q : 31%
 10q : 28%
 17p : 25%

Gene amplification

 PDGFRA
 RNH1
 LRP1
 MET

Gene deletions

 PTEN, CDKN2A, AKT1, CEBPB

References

 Genomic aberrations in pediatric diffuse intrinsic pontine gliomas. Warren KE, Killian K, Suuriniemi M, Wang Y, Quezado M, Meltzer PS. Neuro Oncol. 2011 Nov 7. PMID: #22064882#

 Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ. J Clin Oncol. 2010 Jun 20;28(18):3061-8. PMID: #20479398#

 Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas. Barrow J, Adamowicz-Brice M, Cartmill M, MacArthur D, Lowe J, Robson K, Brundler MA, Walker DA, Coyle B, Grundy R. Neuro Oncol. 2011 Feb;13(2):212-22. PMID: #21138945#

 Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C. J Clin Oncol. 2010 Mar 10;28(8):1337-44. PMID: #20142589#

 Brainstem gliomas—a clinicopathological study of 45 cases with p53 immunohistochemistry. Badhe PB, Chauhan PP, Mehta NK. Indian J Cancer. 2004 Oct-Dec;41(4):170-4. PMID: #15659871# [Free]