Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Hamid Nikbakht, Eshini Panditharatna, Leonie G. Mikael, Rui Li, Tenzin Gayden, Matthew Osmond, Cheng-Ying Ho, Madhuri Kambhampati, Eugene I. Hwang, Damien Faury, Alan Siu, Simon Papillon-Cavanagh, Denise Bechet, Keith L. Ligon, Benjamin Ellezam, Wendy J. Ingram, Caedyn Stinson, Andrew S. Moore, Katherine E. Warren, Jason Karamchandani, Roger J. Packer, Nada Jabado, Jacek Majewski, and Javad Nazarian
Nat Commun. 2016; 7: 11185 PMC4823825
In a recent issue of Nature Communications, Nikbakht, Panditharatna and Mikael et al. published their findings on the genetic landscape of Diffuse Pontine Intrinsic Glioma (DIPG). This was a collaborative effort including investigators from Montreal, Washington DC and Queensland (Australia), examining autopsy brains from 9 DIPG patients. The authors performed Next-Generation sequencing on 134 specimens from various neuroanatomical locations from these patients and showed that the very first genetic aberrations that arise in these tumors are specific mutations in the gene encoding histones (H3) whose role is to package DNA within the nucleus of a cell. These mutations in histone H3K27M have loyal partners in crime in the form of mutations in TP53, PPM1D, ACVR1 and PIK3R1 which are maintained throughout the life of the cancer: from primary tumor, to spread, to the end stage of the disease. Subsequently, the ubiquitous presence of these “clonal” mutations suggests their potential to act as therapeutic targets. Other “subclonal” mutations are picked up on this journey as the tumor spreads outside the brainstem but these alterations may be gained or lost during the course of the disease.
The presence of these specific “oncohistone” mutation partners across time (early and late) and space (primary and different neuroanatomical locations) suggests the role of these genes as driver mutations in DIPG. This publication has significant relevance for patient care because the authors’ findings also advocate the use of needle biopsies as representative of the main drivers in DIPG to orient care. Drs Jabado, Majewski and Nazarian who are the principal investigators of this study propose that efforts to cure DIPG should be directed at the oncohistone partnership.