Glioma progression is shaped by genetic evolution and microenvironment interactions.
Document Type
Article
Publication Date
6-9-2022
Publication Title
Cell
Keywords
JGM, Adult, Brain Neoplasms, Evolution, Molecular, Genes, p16, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasm Recurrence, Local, Tumor Microenvironment
JAX Source
Cell 2022 Jun 9; 185(12):2184-2199.e16
Volume
185
Issue
12
First Page
2184
Last Page
2199
ISSN
1097-4172
PMID
35649412
DOI
https://doi.org/10.1016/j.cell.2022.04.038
Grant
CA034196, NS114873, CA256575, CA252979, CA237208
Abstract
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
Recommended Citation
Varn F,
Johnson K,
Martinek J,
Huse J,
Nasrallah M,
Wesseling P,
Cooper L,
Malta T,
Wade T,
Sabedot T,
Brat D,
Gould P,
Wöehrer A,
Aldape K,
Ismail A,
Sivajothi S,
Barthel F,
Kim H,
Kocakavuk E,
Ahmed N,
White K,
Datta I,
Moon H,
Pollock S,
Goldfarb C,
Lee G,
Garofano L,
Anderson K,
Nehar-Belaid D,
Barnholtz-Sloan J,
Bakas S,
Byrne A,
D'Angelo F,
Gan H,
Khasraw M,
Migliozzi S,
Ormond D,
Paek S,
Van Meir E,
Walenkamp A,
Watts C,
Weiss T,
Weller M,
Palucka K,
Stead L,
Poisson L,
Noushmehr H,
Iavarone A,
Verhaak R.
Glioma progression is shaped by genetic evolution and microenvironment interactions. Cell 2022 Jun 9; 185(12):2184-2199.e16
Comments
We gratefully acknowledge the genome technology, single-cell biology, and microscopy services at the Jackson Laboratory for their expert assistance and Z. Reifsnyder (Jackson Laboratory) for the graphic design. We thank R. Puchalski for his helpful suggestions when designing the histopathology validation studies.