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Glioma progression is shaped by genetic evolution and microenvironment interactions. Cell 2022 Jun 09;185(12):2184-2199.e16

Date

06/02/2022

Pubmed ID

35649412

Pubmed Central ID

PMC9189056

DOI

10.1016/j.cell.2022.04.038

Scopus ID

2-s2.0-85131903367   21 Citations

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.

Author List

Varn FS, Johnson KC, Martinek J, Huse JT, Nasrallah MP, Wesseling P, Cooper LAD, Malta TM, Wade TE, Sabedot TS, Brat D, Gould PV, Wöehrer A, Aldape K, Ismail A, Sivajothi SK, Barthel FP, Kim H, Kocakavuk E, Ahmed N, White K, Datta I, Moon HE, Pollock S, Goldfarb C, Lee GH, Garofano L, Anderson KJ, Nehar-Belaid D, Barnholtz-Sloan JS, Bakas S, Byrne AT, D'Angelo F, Gan HK, Khasraw M, Migliozzi S, Ormond DR, Paek SH, Van Meir EG, Walenkamp AME, Watts C, Weiss T, Weller M, Palucka K, Stead LF, Poisson LM, Noushmehr H, Iavarone A, Verhaak RGW, GLASS Consortium

Authors

Jennifer M. Connelly MD Professor in the Neurology department at Medical College of Wisconsin
Peter LaViolette PhD Associate Professor in the Radiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Brain Neoplasms
Evolution, Molecular
Genes, p16
Glioma
Humans
Isocitrate Dehydrogenase
Mutation
Neoplasm Recurrence, Local
Tumor Microenvironment