Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics
Hoffman LM, DeWire M, Ryall S, Buczkowicz P, Leach J, Miles L, Ramani A, Brudno M, Kumar SS, Drissi R, Dexheimer P, Salloum R, Chow L, Hummel T, Stevenson C, Lu QR, Jones B, Witte D, Aronow B, Hawkins CE, Fouladi M
Acta Neuropathologica Communications (2016) 4:1
Hoffman, DeWire, and Ryall et al. recently published results of a collaborative study between Cincinnati Children’s Hospital Medical Center and The Hospital for Sick Children describing genetic characteristics of diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) from different regions of tumor within the same patient at autopsy. They performed whole exome sequencing on matched tumor samples from the primary tumor and metastatic sites from 8 patients, including 7 DIPGs and 1 mHGG. Infiltration of tumor into adjacent brain structures and distant metastatic spread was common. Most tumors exhibited histological variation both within the primary tumor and between the primary tumor and metastatic sites, suggesting poor reliability of histopathological grading (e.g. a pathologist’s determination of the aggressiveness of tumor by looking under a microscope). Certain genetic abnormalities were conserved across all tumor locations, including prognostically relevant mutations in H3F3A (H3.3) and HIST1H3B (H3.1), as well as mutations in ACVR1, PIK3CA, FGFR1, and MET. The uniform presence of these mutations across all disease sites implies that they are more likely genetic “drivers” and potentially better therapeutic targets. Other genetic abnormalities, including mutations in PDGFRA, ATRX, and BCOR, were found in some tumor locations but not others. These genetic mutations are likely “subclonal”, meaning that the tumor may gain or lose these genetic defects throughout the disease process, making them less promising therapeutic targets. This publication is important not only for defining the best therapeutic strategy but also for advocating broader implementation of diagnostic biopsy for DIPG and mHGG (at centers with adequate neurosurgical expertise), since information gained from molecular characterization of biopsy tissue may be both prognostically and therapeutically valuable.