diffuse intrinsic pontine glioma

Definition: 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.

Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account for 10% to 25% of pediatric brain tumors.

The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years.

Dysregulation of EGFR and p53 may play an important role in the development of DIPGs. (24076776)

The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment. (24076776)

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

 Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Ballester LY, Wang Z, Shandilya S, Miettinen M, Burger PC, Eberhart CG, Rodriguez FJ, Raabe E, Nazarian J, Warren K, Quezado MM. Am J Surg Pathol. 2013 Sep;37(9):1357-64. doi : 10.1097/PAS.0b013e318294e817 PMID: 24076776

 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]