NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings

Brett J Theeler^{1

2}, Yamini Dalal³, Michelle Monje⁴, Ali Shilatifard⁵, Mario L Suvà^{6

7}, Orwa Aboud², Kevin Camphausen⁸, Christine Cordova², Elizabeth Finch⁹, John D Heiss¹⁰, Roger J Packer^{9

11}, Carlos G Romo², Kenneth Aldape¹², Marta Penas-Prado², Terri Armstrong², Mark R Gilbert²

Affiliations

¹ Department of Neurology and John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
² Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
³ Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Stanford University Hospital, Departments of Neurology, Neurosurgery, Pathology, and Pediatrics, Palo Alto, California, USA.
⁵ Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
⁶ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁸ Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁹ Brain Tumor Institute, Children's National Health System, Washington, District of Columbia, USA.
¹⁰ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
¹¹ Center for Neuroscience and Behavioral Health, Children's National Health System, Washington, District of Columbia, USA.
¹² Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 32642676
PMCID: PMC7212875
DOI: 10.1093/noajnl/vdaa007

Review

NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings

Brett J Theeler et al. Neurooncol Adv. 2020.

. 2020 Jan 16;2(1):vdaa007.

doi: 10.1093/noajnl/vdaa007. eCollection 2020 Jan-Dec.

Authors

Affiliations

¹ Department of Neurology and John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
² Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
³ Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Stanford University Hospital, Departments of Neurology, Neurosurgery, Pathology, and Pediatrics, Palo Alto, California, USA.
⁵ Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
⁶ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁸ Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁹ Brain Tumor Institute, Children's National Health System, Washington, District of Columbia, USA.
¹⁰ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
¹¹ Center for Neuroscience and Behavioral Health, Children's National Health System, Washington, District of Columbia, USA.
¹² Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 32642676
PMCID: PMC7212875
DOI: 10.1093/noajnl/vdaa007

Abstract

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Keywords: NCI-CONNECT; clinical trials; histone-mutated glioma; rare brain tumors.

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Figures

**Fig. 1**
Schematic illustrating the bidirectional relationship between normal neural cells and their malignant glioma counterparts. Activity-related factors, including a secreted form of neuroligin-3 (sNLGN3) from normal oligodendrocyte progenitor cells (OPCs, blue) and neurons (yellow) and neurotrophins such as BDNF, fuel the growth of glioma. Disentegrin and metalloproteinase domain-containing protein 10 (ADAM10, not shown in figure) cleaves neuroligin-3 before it is released into extracellular space. Adapted from ref. with permission.

**Fig. 2**
(A) Pairwise correlation between the average expression profiles of malignant cells from 25 gliomas, ordered by hierarchical clustering (top) and marked by clinical classification (color bar). (B–E) Differentially expressed genes across gliomas, including H3K27M-mutant gliomas (as seen on the green bars in A and B). (E) Note the enrichment of PRC2 targets in each subset of differentially expressed genes (Fisher’s exact test), with enrichment of PRC2 targets reaching the highest level of statistical significance in the K27M-mutant gliomas. Adapted from ref. with permission.

See this image and copyright information in PMC

References

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NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings

Affiliations

NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings

Authors

Affiliations

Abstract

Figures

References

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