Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma

M.-M Georgescu,C M Notarianni,Y Li,D K Burns,M L Circu,M Z Islam,J Traylor,C N Kline

doi:10.1186/s40478-020-00992-9

M.-M Georgescu, C M Notarianni + Show 6 more

Open Access

https://doi.org/10.1186/s40478-020-00992-9

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Abstract

Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

Highlights

Diffuse midline glioma with histone H3-K27M mutation (DMG/K27M) is a newly defined entity in the World Health Organization (WHO) group of grade IV diffuse gliomas, usually seen in the pediatric population [1]
F5 initially complained of daily headaches and recurrent ear and sinus infections, followed by behavioral changes manifested by extreme anger, and right eye strabismus
Magnetic resonance imaging (MRI) showed a 5.5 × 5.0 × 3.9 cm, non-enhancing, pontine mass with secondary hydrocephalus of 4th and 3rd ventricles that was radiologically diagnosed as diffuse intrinsic pontine gliomas (DIPG) without biopsy

Summary

Introduction

Diffuse midline glioma with histone H3-K27M mutation (DMG/K27M) is a newly defined entity in the World Health Organization (WHO) group of grade IV diffuse gliomas, usually seen in the pediatric population [1]. Most of these tumors occur in the pons, as diffuse intrinsic pontine gliomas (DIPG), and a smaller proportion occur in the thalamus, cerebellum or spinal cord [2]. Most of these studies relied on pontine biopsies, and only limited studies addressed the spatiotemporal evolution of DIPG, mainly within infratentorial foci [13, 17]

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