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Analysis of a progressive diffuse intrinsic pontine glioma: a case report

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What’s Known
Despite multiple clinical trials testing an assortment of new treatments, the survival rate for diffuse intrinsic pontine glioma (DIPG) remains abysmal, with most children succumbing to the pediatric brainstem tumor within 12 months of diagnosis. Focal radiation therapy, the primary treatment approach, has not improved overall survival. While the majority of DIPG tumors grow within the brainstem, metastases can occur elsewhere in the brain. Due to recent availability of tissue, new data are emerging about the biologic behavior of tumors, details that could be instrumental in constructing optimal treatment strategies.

What’s New
An otherwise healthy 9-year-old girl developed weakness in the left side of her face; magnetic resonance imagining revealed T2/FLAIR hyperintensity centered within and expanding the pons. Despite various treatments, her pontine lesion increased in size and new metastases were noted. The team led by Children’s National Health System researchers is the first to report comprehensive phenotypic analyses comparing multiple sites in primary and distant tumors. All tumor sites displayed positive staining for the H3K27M mutation, a mutation described in more than two-thirds of DIPGs that may portend a worse overall survival. Persistence of mutational status across multiple metastatic sites is particularly important since the effectiveness of some therapeutic approaches relies on this occurring. mRNA analyses, by contrast, identified a small number of genes in the primary tumor that differed from one metastatic tumor. This divergence implies that a single biopsy analysis for mRNA expression has the potential to be misleading.

Questions for Future Research
Q: Because a small cohort of genes in the girl’s primary tumor were different from genes in portions of the metastatic tumor, would genomic and proteomic analyses provide additional details about this genetic evolution?
Q: How do site-specific differences in mRNA expression affect decisions about which therapies to provide and in which order?

Source: Histological and Molecular Analysis of a Progressive Diffuse Intrinsic Pontine Glioma and Synchronous Metastatic Lesions: A Case Report.” J. Nazarian, G.E. Mason, C.Y. Ho, E. Panditharatna, M. Kambhampati, L.G. Vezina, R.J. Packer, and E.I. Hwang. Published by Oncotarget on June 14, 2016.

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

What’s Known
Needle biopsies help to guide diagnosis and targeted therapies for diffuse intrinsic pontine gliomas (DIPGs), which make up 10 percent to 15 percent of all pediatric brain tumors but carry a median survival of 9 to 12 months. This dismal survival rate compares with a 70 percent chance of children surviving other central nervous system tumors five years post diagnosis. In DIPG, tumors appear in the pons, an area of the brain that houses cranial nerve nuclei. Surgical options are limited. Spatial and temporal tumor heterogeneity is a major obstacle to accurate diagnosis and successful targeted therapy.

What’s New
The team sought to better define DIPG heterogeneity. They analyzed 134 specimens from nine patients and found that H3K27M mutations were ubiquitous in all 41 samples with oncogenic content, and always were associated with at least one partner driver mutation: TP53, PPM1D, ACVR1 or PIK3R1. These H3K27M mutations are the initial oncogenic event in DIPG, writes the research team led by Children’s National Health System. “Driver” mutations, such as H3K27M, are essential to begin and sustain tumor formation. This main driver partnership is maintained throughout the course of the disease, in all cells across the tumor, and as tumors spread throughout the brain. Because homogeneity for main driver mutations persists for the duration of illness, efforts to cure DIPG should be directed at the oncohistone partnership, the authors write. Based on early tumor spread, efforts to cure DIPG should aim for early systemic tumor control, rather focused exclusively on the pons.

Questions for Future Research
Q: If a larger sample size were analyzed, what would it reveal about the true heterogeneity/homogeneity status of DIPGs?
Q: “Accessory” driver mutations are not absolutely essential but do help to further promote and accelerate tumor growth. What is their precise role?

Source: Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pontine Glioma.” H. Nikbakht, E. Panditharatna, L.G. Mikael, R. Li, T. Gayden, M. Osmond, C.Y. Ho, M. Kambhampati, E.I. Hwang, D. Faury, A. Siu, S. Papillon-Cavanagh, D. Bechet, K.L. Ligon, B. Ellezam, W.J. Ingram, C. Stinson, A.S. Moore, K.E. Warren, J. Karamchandani, R.J. Packer, N. Jabado, J. Majewski, and J. Nazarian. Published by Nature Communications on April 6, 2016.