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

Acta Neuropathologica Communications

Mariko DeWire¹  Xiaoting Zhu¹  Margot A. Lazow¹  Austin Schafer¹  Allison Bartlett¹  Deepak Kumar Mishra²  Shiva Senthil Kumar²  Phillip Dexheimer³  Christine Fuller⁴  James L. Leach⁵  Rachid Drissi⁶  Maryam Fouladi⁶ 

[1] Brain Tumor Center, Division of Oncology, Cincinnati Children’s Hospital Medical Center;Center for Childhood Cancer & Blood Disorders, Nationwide Children’s Hospital;Department of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center;Department of Pathology, Upstate Medical University;Department of Radiology and Medical Imaging, Cincinnati Children’s Hospital Medical Center;The Ohio State University College of Medicine;

关键词: Radiogenomics;    DIPG;    Serial MR imaging;    Overall survival;    Molecular subgrouping;   

DOI  :  10.1186/s40478-020-01107-0

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown