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Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of Clusterin (CLU), Elongation Factor 2 (EF2), and Talin-1 (TLN1) in DIPGs studied. Comparisons to mRNA expression profiles generated from tumor and adjacent normal brain tissue indicated two DIPG subgroups, characterized by upregulation of Myc (N-Myc) or Hedgehog (Hh) signaling. We validated upregulation of PTCH, a membrane receptor in the Hh signaling pathway, in a subgroup of DIPG specimens. DNA methylation analysis indicated global hypomethylation of DIPG compared to adjacent normal tissue specimens, with differential methylation of 24 genes involved in Hh and Myc pathways, correlating with protein and mRNA expression patterns. Sequencing analysis showed c.83A>T mutations in the H3F3A or HIST1H3B gene in 77 % of our DIPG cohort. Supervised analysis revealed a unique methylation pattern in mutated specimens compared to the wild-type DIPG samples. This study presents the first comprehensive multidimensional protein, mRNA, and methylation profiling of pediatric brain tumor specimens, detecting the presence of two subgroups within our DIPG cohort. This multidimensional analysis of DIPG provides increased analytical power to more fully explore molecular signatures of DIPGs, with implications for evaluating potential molecular subtypes and biomarker discovery for assessing response to therapy.

SUBMITTER: Saratsis AM

PROVIDER: S-EPMC4028366 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.

Saratsis Amanda M AM Kambhampati Madhuri M Snyder Kendall K Yadavilli Sridevi S Devaney Joseph M JM Harmon Brennan B Hall Jordan J Raabe Eric H EH An Ping P Weingart Melanie M Rood Brian R BR Magge Suresh N SN MacDonald Tobey J TJ Packer Roger J RJ Nazarian Javad J

Acta neuropathologica 20131203 6

Diffuse intrinsic pontine glioma (DIPG) is a highly morbid form of pediatric brainstem glioma. Here, we present the first comprehensive protein, mRNA, and methylation profiles of fresh-frozen DIPG specimens (n = 14), normal brain tissue (n = 10), and other pediatric brain tumors (n = 17). Protein profiling identified 2,305 unique proteins indicating distinct DIPG protein expression patterns compared to other pediatric brain tumors. Western blot and immunohistochemistry validated upregulation of ...[more]

PMID: 24297113

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Project description:Abstract PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p?0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p?0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.

Dataset Information

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.

Publications

Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.

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