A pilot radiogenomic study of DIPG reveals distinct subgroups with unique clinical trajectories and therapeutic targets.
Xiaoting ZhuMargot A LazowAustin SchaferAllison BartlettShiva Senthil KumarDeepak Kumar MishraPhillip DexheimerMariko DeWireChristine FullerJames L LeachMaryam FouladiRachid DrissiPublished in: Acta neuropathologica communications (2021)
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.
Keyphrases
- end stage renal disease
- ejection fraction
- newly diagnosed
- copy number
- chronic kidney disease
- magnetic resonance imaging
- depressive symptoms
- early stage
- radiation induced
- prognostic factors
- single cell
- stem cells
- peritoneal dialysis
- computed tomography
- oxidative stress
- clinical trial
- lymph node
- climate change
- randomized controlled trial
- gene expression
- magnetic resonance
- squamous cell carcinoma
- mass spectrometry
- poor prognosis
- cell proliferation
- dna methylation
- single molecule
- patient reported outcomes
- contrast enhanced
- long non coding rna
- ultrasound guided
- risk assessment
- genome wide
- fine needle aspiration
- diffusion weighted imaging