A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets

Xiaoting Zhu,Phillip Dexheimer,Austin Schafer,Christine Fuller,Allison Bartlett,Rachid Drissi,Mariko Dewire,Deepak Kumar Mishra,Shiva Senthil Kumar,Margot A Lazow,James L Leach,Maryam Fouladi

doi:10.1186/s40478-020-01107-0

Abstract

An adequate understanding of the relationships between radiographic and genomic features in diffuse intrinsic pontine glioma (DIPG) is essential, especially in the absence of universal biopsy, to further characterize the molecular heterogeneity of this disease and determine which patients are most likely to respond to biologically-driven therapies. Here, a radiogenomics analytic approach was applied to a cohort of 28 patients with DIPG. Tumor size and imaging characteristics from all available serial MRIs were evaluated by a neuro-radiologist, and patients were divided into three radiographic response groups (partial response [PR], stable disease [SD], progressive disease [PD]) based on MRI within 2 months of radiotherapy (RT) completion. Whole genome and RNA sequencing were performed on autopsy tumor specimens. We report several key, therapeutically-relevant findings: (1) Certain radiologic features on first and subsequent post-RT MRIs are associated with worse overall survival, including PD following irradiation as well as present, new, and/or increasing peripheral ring enhancement, necrosis, and diffusion restriction. (2) Upregulation of EMT-related genes and distant tumor spread at autopsy are observed in a subset of DIPG patients who exhibit poorer radiographic response to irradiation and/or higher likelihood of harboring H3F3A mutations, suggesting possible benefit of upfront craniospinal irradiation. (3) Additional genetic aberrations were identified, including DYNC1LI1 mutations in a subgroup of patients with PR on post-RT MRI; further investigation into potential roles in DIPG tumorigenesis and/or treatment sensitivity is necessary. (4) Whereas most DIPG tumors have an immunologically “cold” microenvironment, there appears to be a subset which harbor a more inflammatory genomic profile and/or higher mutational burden, with a trend toward improved overall survival and more favorable radiographic response to irradiation, in whom immunotherapy should be considered. This study has begun elucidating relationships between post-RT radiographic response with DIPG molecular profiles, revealing radiogenomically distinct subgroups with unique clinical trajectories and therapeutic targets.

Highlights

Despite recent advances providing valuable insight into the underlying biology of diffuse intrinsic pontine glioma (DIPG), the most common brainstem tumor of childhood, prognosis remains dismal, with median overall survival less than 12 months [2, 30, 42]
Clinical cohort This retrospective radiogenomics study was approved by the Institutional Review Board (IRB) at Cincinnati Children’s Hospital Medical Center (CCHMC; IRB ID: 2019– 1220) and included patients enrolled on the CCHMC investigator-initiated Pediatric Brain Tumor Repository (PBTR), a multidisciplinary approach to pediatric brain tumor autopsy donation [19]
Utilizing MR imaging within 2 months of completion of irradiation, patients were divided into three radiographic disease response groups (PR, SD, progressive disease (PD)) based on established Response Assessment in Neuro-Oncology (RANO) and Response Assessment in Pediatric NeuroOncology (RAPNO) criteria [13, 14]

Summary

Introduction

Despite recent advances providing valuable insight into the underlying biology of diffuse intrinsic pontine glioma (DIPG), the most common brainstem tumor of childhood, prognosis remains dismal, with median overall survival less than 12 months [2, 30, 42]. While clinical trials over the past decades have failed to improve outcomes for patients with DIPG, growing knowledge of the genetic and epigenetic drivers of this disease may facilitate new targeted therapies as well as classification into biologically and clinically distinct subtypes [7, 71, 72]. In order to further characterize the molecular and clinical heterogeneity of this disease and determine which patients are most likely to respond to biologically-driven therapies, especially in the absence of universal diagnostic biopsy, an improved understanding of the relationships between radiographic and genomic characteristics in DIPG will be critically important

Methods

Results

Conclusion