Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics

Abstract

IntroductionDiffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization.ResultsMedian age at diagnosis was 6.1 years (range: 2.9–23.3 years). Median overall survival was 13.2 months (range: 11.2–32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. ConclusionSpatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0269-0) contains supplementary material, which is available to authorized users.

Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models

“…Institutional rapid autopsy programs have been well described 1,3–12 and have previously led to significant advances in cancer research in the areas of prostate, 1,3,4,6,7,11 pancreas, 10 breast, 8 and pediatric brain tumors. 5,9,12 This program builds on prior autopsy programs by enrolling patients of all ages and cancer types, capturing samples throughout a patient’s disease course, and leveraging multiple parallel platforms to generate high-throughput sequencing data and robust preclinical tumor models.…”

“…5,9,12 This program builds on prior autopsy programs by enrolling patients of all ages and cancer types, capturing samples throughout a patient’s disease course, and leveraging multiple parallel platforms to generate high-throughput sequencing data and robust preclinical tumor models. We highlight our initial experience with 15 patients who underwent rapid autopsy and emphasize the following three themes: capturing the molecular status of a diverse set of neoplasms at the end point in disease progression relative to samples acquired earlier in the course of disease; the comparison of primary tumors to a multiplicity of metastatic sites at the molecular level to study processes underlying metastatic spread and organ-specific tumor tropism; and the development of tumor organoid models 2 and patient-derived xenografts (PDXs), with the potential for high-throughput drug screening and functional validation studies.…”

Multimodal evaluation demonstrates in vivo 18F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration

“…18 F-AV-1451 is a PET radioligand that achieves in vivo binding in Alzheimer's disease (AD)[8] and autoradiographic evidence of binding to paired helical filaments (PHFs) composed of 3-repeat misfolded tau (3Rtau) and 4Rtau characteristic of AD histopathology[4, 5, 7]. However, autoradiographic studies of 18 F-AV-1451 on CBD post-mortem tissue failed to demonstrate binding in cortical regions[5, 7] though there was minimal pathology in one study (<1.1% tau-load)[7].…”

“…However, autoradiographic studies of 18 F-AV-1451 on CBD post-mortem tissue failed to demonstrate binding in cortical regions[5, 7] though there was minimal pathology in one study (<1.1% tau-load)[7]. Another study suggests minimal, but present, autoradiographic binding of 18 F-AV-1451 for 4Rtau[4]. Given mixed autoradiographic evidence in CBD, there is a need for in vivo evaluations of 18 F-AV-1451 in patients with pathological-confirmation.…”

MRI and PET: Noninvasive Tools to Probe the Biology of Diffuse Intrinsic Pontine Glioma

“…One of the biggest challenges to developing effective treatments has been the lack of tissue for analysis because the location of the tumor within the brain stem is difficult to access surgically. Recent studies using biopsy or autopsy specimens are changing this landscape and shedding light on distinct genetic changes in brain stem gliomas, such as mutations in genes encoding histones (2). As a result, the 2016 revised World Health Organization classification of brain tumors includes an entity for H3K27M-mutant diffuse midline glioma (3).…”