Hg-72dipg Cells Escape the Pons Early During Tumour Evolution
Year: 2016
Type: article
Abstract: With the opening of rapid autopsy protocols for the biological study of diffuse intrinsic pontine glioma (DIPG), it has been shown that these highly infiltrative lesions may be found outside the pons and spread throughout the central nervous system at the time of death. We carried out exome and high depth targeted resequencing of multiple samples from distinct anatomical locations from individual patients in order to evaluate the spatial heterogeneity of these tumours. Comparing the cancer cell fractions from across a given tumour sample clearly demonstrated both the ubiquitous presence of presumed early driver alterations (H3F3A, HIST1H3B, ACVR1) but also a range of mutations private to only one portion of the tumour – these included those occurring only at the point of escape of cells from the brainstem, such as mutations in WNK2, known to play a role in glioma cell migration and invasion. Reconstructing tumour phylogenies revealed a branching evolutionary trajectories and implied a predominantly early migration outside the pons, with distant tumour locations displaying evidence of convergent evolution in key oncogenic drivers such as PIK3CA, NF1, MKI67, NOTCH1 and DMNT3A. This has important implications for locally delivered therapies, and re-opens the debate for the use of whole brain irradiation upfront in children with DIPG. The later acquisition of convergent mutations in genes controlling key signalling pathways associated with proliferation at these distant sites also underlies the challenges in preventing tumour recurrence and/or metastasis at anatomically distinct sites in the central nervous system.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2429140989