Glioma progression is shaped by genetic evolution and microenvironment interactions

• DOI: 10.1016/j.cell.2022.04.038
• Publication Date: 2022-05-31T14:54:33Z
• Authors: Frederick S. Varn; Kevin C. Johnson; Jan Martinek; Jason T. Huse; MacLean P. Nasrallah; Pieter Wesseling; Lee A.D. Cooper; Tathiane M. Malta; Taylor E. Wade; Thais S. Sabedot; Daniel Brat; Peter V. Gould; Adelheid Wöehrer; Kenneth Aldape; Azzam Ismail; Santhosh K. Sivaj...; Floris P. Barthel; Hoon Kim; Emre Kocakavuk; Nazia Ahmed; Kieron White; Indrani Datta; Hyo-Eun Moon; Steven Pollock; Christine Goldfarb; Ga-Hyun Lee; Luciano Garofano; Kevin J. Anderson; Djamel Nehar-Belaid; Jill S. Barnholtz...; Spyridon Bakas; Annette T. Byrne; Fulvio D’Angelo; Hui K. Gan; Mustafa Khasraw; Simona Migliozzi; D. Ryan Ormond; Sun Ha Paek; Erwin G. Van Meir; Annemiek M.E. Wal...; Colin Watts; Tobias Weiss; Michael Weller; Karolina Palucka; Lucy F. Stead; Laila M. Poisson; Houtan Noushmehr; Antonio Iavarone; Roel G.W. Verhaak; Frederick S. Varn; Kevin C. Johnson; Jan Martinek; Jason T. Huse; MacLean P. Nasrallah; Pieter Wesseling; Lee A.D. Cooper; Tathiane M. Malta; Taylor E. Wade; Thais S. Sabedot; Daniel Brat; Peter V. Gould; Adelheid Wöehrer; Kenneth Aldape; Azzam Ismail; Santhosh K. Sivaj...; Floris P. Barthel; Hoon Kim; Emre Kocakavuk; Nazia Ahmed; Kieron White; Indrani Datta; Hyo-Eun Moon; Steven Pollock; Christine Goldfarb; Ga-Hyun Lee; Luciano Garofano; Kevin J. Anderson; Djamel Nehar-Belaid; Jill S. Barnholtz...; Spyridon Bakas; Annette T. Byrne; Fulvio D’Angelo; Hui K. Gan; Mustafa Khasraw; Simona Migliozzi; D. Ryan Ormond; Sun Ha Paek; Erwin G. Van Meir; Annemiek M.E. Wal...; Colin Watts; Tobias Weiss; Michael Weller; Kristin D. Alfaro; Samirkumar B. Amin; David M. Ashley; Christoph Bock; Andrew Brodbelt; Ketan R. Bulsara; Ana Valeria Castro; Jennifer M. Connelly; Joseph F. Costello; John F. de Groot; Gaetano Finocchiaro; Pim J. French; Anna Golebiewska; Ann C. Hau; Chibo Hong; Craig Horbinski; Kasthuri S. Kannan; Mathilde CM. Kouw...; Anna Lasorella; Peter S. LaViolette; Keith L. Ligon; Allison K. Lowman; Shwetal Mehta; Hrvoje Miletic; Annette M. Molinaro; Ho Keung Ng; Simone P. Niclou; Johanna M. Niers; Joanna J. Phillips; Raul Rabadan; Ganesh Rao; Guido Reifenberger; Nader Sanai; Susan C. Short; Peter Sillevis Smitt; Andrew E. Sloan; Marion Smits; James M. Snyder; Hiromichi Suzuki; Ghazaleh Tabatabai; Georgette Tanner; William H. Tomasz...; Michael Wells; Bart A. Westerman; Helen Wheeler; Jichun Xie; W.K. Alfred Yung; Gelareh Zadeh; Junfei Zhao; Karolina Palucka; Lucy F. Stead; Laila M. Poisson; Houtan Noushmehr; Antonio Iavarone; Roel GW. Verhaak
• Keywords: Medizin; neurons; p16; Medical and Health Sciences; Medicine and Health Sciences; Tumor Microenvironment; 2.1 Biological and endogenous factors; spatial imaging; Cancer; 0303 health sciences; JGM; Brain Neoplasms; Life Sciences; Glioma; Biological Sciences; Isocitrate Dehydrogenase; GLASS Consortium; macrophages; 3. Good health; Local; Adult; 570; Evolution; Oncology and Carcinogenesis; 610; treatment resistance; Evolution, Molecular; 03 medical and health sciences; Cancer Genomics; Rare Diseases; Genetics; genomics; Humans; Biomedical and Clinical Sciences; Genes, p16; Human Genome; hypermutation; Neurosciences; glioblastoma; Molecular; single-cell; microenvironment; Brain Disorders; Brain Cancer; Neoplasm Recurrence; Genes; Mutation; Neoplasm Recurrence, Local; Developmental Biology

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.