Glioma progression is shaped by genetic evolution and microenvironment interactions
Frederick S. Varn(Jackson Laboratory), Kevin C. Johnson(Jackson Laboratory), Jan Martinek(Jackson Laboratory), Jason T. Huse(The University of Texas MD Anderson Cancer Center), MacLean P. Nasrallah(University of Pennsylvania), Pieter Wesseling(Princess Máxima Center), Lee Cooper(Northwestern University), Tathiane M. Malta(Universidade de São Paulo), Taylor Wade(Jackson Laboratory), Thaís S. Sabedot(Henry Ford Health System), Daniel J. Brat(Northwestern University), Peter V. Gould(Hôpital de l'Enfant-Jésus), Adelheid Wöehrer(Medical University of Vienna), Kenneth Aldape(National Cancer Institute), Azzam Ismail(St James's University Hospital), Santhosh Sivajothi(Jackson Laboratory), Floris P Barthel(Translational Genomics Research Institute), Hoon Kim(Jackson Laboratory), Emre Kocakavuk(Jackson Laboratory), Nazia Ahmed(University of Leeds), Kieron White(Royal College of Surgeons in Ireland), Indrani Datta(Henry Ford Health System), Hyo-Eun Moon(Seoul National University Hospital), Steven Pollock(University of Leeds), Christine N. Goldfarb(Jackson Laboratory), Ga-Hyun Lee(Jackson Laboratory), Luciano Garofano(Columbia University Irving Medical Center), Kevin Anderson(Jackson Laboratory), Djamel Nehar-Belaid(Jackson Laboratory), Jill S. Barnholtz‐Sloan(University Hospitals of Cleveland), Spyridon Bakas(University of Pennsylvania), Annette T. Byrne(Royal College of Surgeons in Ireland), Fulvio D’Angelo(Columbia University Irving Medical Center), Hui K. Gan(Olivia Newton-John Cancer Wellness & Research Centre), Mustafa Khasraw(Duke Medical Center), Simona Migliozzi(Columbia University Irving Medical Center), D. Ryan Ormond(University of Colorado Denver), Sun Ha Paek(Seoul National University Hospital), Erwin G. Van Meir(University of Alabama at Birmingham), Annemiek Walenkamp(University Medical Center Groningen), Colin Watts(University of Birmingham), Tobias Weiss(University of Zurich), Michael Weller(University of Zurich), Karolina Palucka(Jackson Laboratory), Lucy F. Stead(University of Leeds), Laila Poisson(Henry Ford Health System), Houtan Noushmehr(Henry Ford Health System), Antonio Iavarone(Columbia University Irving Medical Center), Roel G.W. Verhaak(Jackson Laboratory), Frederick S. Varn(Jackson Laboratory), Kevin C. Johnson(Jackson Laboratory), Jan Martinek(Jackson Laboratory), Jason T. Huse(The University of Texas MD Anderson Cancer Center), MacLean P. Nasrallah(University of Pennsylvania), Pieter Wesseling(Princess Máxima Center), Lee Cooper(Northwestern University), Tathiane M. Malta(Universidade de São Paulo), Taylor Wade(Jackson Laboratory), Thaís S. Sabedot(Henry Ford Health System), Daniel J. Brat(Northwestern University), Peter V. Gould(Hôpital de l'Enfant-Jésus), Adelheid Wöehrer(Medical University of Vienna), Kenneth Aldape(National Cancer Institute), Azzam Ismail(St James's University Hospital), Santhosh Sivajothi(Jackson Laboratory), Floris P Barthel(Translational Genomics Research Institute), Hoon Kim(Jackson Laboratory), Emre Kocakavuk(Jackson Laboratory), Nazia Ahmed(University of Leeds), Kieron White(Royal College of Surgeons in Ireland), Indrani Datta(Henry Ford Health System), Hyo-Eun Moon(University of Leeds), Steven Pollock(University of Leeds), Christine N. Goldfarb(Jackson Laboratory), Ga-Hyun Lee(Columbia University Irving Medical Center), Luciano Garofano(Columbia University Irving Medical Center), Kevin Anderson(Jackson Laboratory), Djamel Nehar-Belaid(University Hospitals of Cleveland), Jill S. Barnholtz‐Sloan(University Hospitals of Cleveland), Spyridon Bakas(Royal College of Surgeons in Ireland), Annette T. Byrne(Royal College of Surgeons in Ireland), Fulvio D’Angelo(Olivia Newton-John Cancer Wellness & Research Centre), Hui K. Gan(Duke Medical Center), Mustafa Khasraw(Columbia University Irving Medical Center), Simona Migliozzi(Columbia University Irving Medical Center), D. Ryan Ormond(Seoul National University Hospital), Sun Ha Paek(Seoul National University Hospital), Erwin G. Van Meir(University Medical Center Groningen), Annemiek Walenkamp(University Medical Center Groningen), Colin Watts(University of Zurich), Tobias Weiss(University of Zurich), Michael Weller(University of Zurich), Kristin Alfaro-Munoz, Samirkumar B. Amin, David M. Ashley, Christoph Bock, Andrew Brodbelt, Ketan R. Bulsara, Ana Valéria Castro, Jennifer Connelly, J Costello, John F. de Groot, Gaetano Finocchiaro, Pim J. French(University of Pennsylvania), Anna Golebiewska, Ann‐Christin Hau, Chibo Hong, Craig Horbinski, Kasthuri Kannan, Mathilde C.M. Kouwenhoven(University of Pennsylvania), Anna Lasorella, Peter S. LaViolette, Keith L. Ligon, Allison Lowman, Shwetal Mehta, Hrvoje Miletić, Annette M. Molinaro(University of Alabama at Birmingham), Ho‐Keung Ng, Simone P. Niclou, Johanna M. Niers, Joanna J. Phillips, Raúl Rabadán, Ganesh Rao, Guido Reifenberger, Nader Sanai, Susan Short(Hôpital de l'Enfant-Jésus), Peter Sillevis Smitt(University Hospitals of Cleveland), Andrew E. Sloan, Marion Smits, James M. Snyder, Hiromichi Suzuki, Ghazaleh Tabatabai, Georgette Tanner, William H. Tomaszewski(University of Zurich), Michael Wells(Translational Genomics Research Institute), Bart A. Westerman, Helen Wheeler, Jichun Xie, W.K. Alfred Yung, Gelareh Zadeh, Junfei Zhao(Jackson Laboratory), Karolina Palucka(University of Leeds), Lucy F. Stead(University of Leeds), Laila Poisson(Henry Ford Health System), Houtan Noushmehr(Henry Ford Health System), Antonio Iavarone(Columbia University Irving Medical Center), Roel G.W. Verhaak(Amsterdam University Medical Centers)
Cited by 486Open Access
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.
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