Divergent genomic evolution in astrocytomas and oligodendrogliomas

Astrocytomas and oligodendrogliomas are isocitrate dehydrogenase (IDH)-mutant gliomas that most commonly arise in adults under the age of 50 and exhibit variable responses to treatment1–3. To understand the genetic drivers of disease progression, here we used whole-genome and whole-exome sequencing to characterize longitudinally collected tumour specimens from 183 patients with IDH-mutant glioma. Samples were collected through the Glioma Longitudinal Analysis (GLASS) Consortium4. Most primary surgery samples were classified as grade 2 on the basis of histology (73% for astrocytomas and 93% for oligodendrogliomas). We validated known genomic markers of tumour progression, including hypermutation and homozygous deletion of CDKN2A or CDKN2B (hereafter, CDKN2A/B)5, and discovered genetic alterations that distinguish between the evolutionary trajectories of astrocytomas and those of oligodendrogliomas. Mutations in phosphatidylinositol 3-kinase (PI3K) and NOTCH1 were newly acquired in recurrent oligodendrogliomas, regardless of treatment, and were associated with an increased tumour mutational burden. In recurrent astrocytomas, however, again irrespective of treatment, acquired focal oncogene amplifications and CDKN2A/B homozygous deletions were associated with an increase in chromosomal imbalances, which converged with markers of chromosomal instability such as chromothripsis and whole-genome doubling. In both types of IDH-mutant glioma, we observed a convergence of acquired alterations, genome-wide changes and worse patient outcomes, suggesting that treatment-refractory clones were being selected. Treatment with temozolomide was associated with the mutational signatures SBS11 and SBS119 in both tumour types, whereas the radiotherapy-associated ID8 signature increased in astrocytomas specifically. We show that the genomes of oligodendrogliomas and astrocytomas adapt to the selective pressures of tumour progression and treatment in distinct ways, suggesting that oligodendrogliomas and astrocytomas differ in their responses to treatment-induced DNA damage. Longitudinal genomic analyses in patients with astrocytoma or oligodendrioglioma suggest that these two types of tumour differ in the mechanisms by which they become resistant to treatment, with astrocytomas accumulating copy-number alterations and chromosomal instability markers but oligodendrogliomas acquiring new driver mutations.

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Journal
Nature
Published
2026-10-14
DOI
https://doi.org/10.1038/s41586-026-11150-x
Primary Topic
Glioma Diagnosis and Treatment
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article
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article

Divergent genomic evolution in astrocytomas and oligodendrogliomas

Wies Vallentgoed, Annemiek Walenkamp, Kathleen McCortney, Andrew R. Brodbelt et al.
Nature
Glioma Diagnosis and Treatment
article

Divergent genomic evolution in astrocytomas and oligodendrogliomas

Wies Vallentgoed, Annemiek Walenkamp, Kathleen McCortney, Andrew R. Brodbelt, Mustafa Khasraw, Simona Migliozzi, W.K. Alfred Yung, Emre Kocakavuk, Gordon Y. Ye, Adelheid Wöehrer, David Ryan Ormond, Craig Horbinski, Keith Lloyd Ligon, Hui Kong Gan, Floris P Barthel, Padmaja L. Ghospurkar, Luciano Garofano, Guido Reifenberger, Tobias Weiß, Michael Weller, Ganesh Rao, Frederick S. Varn, Pim J. French, Jason T. Huse, Taylor E. Wade, Fulvio D’Angelo, E. Zeynep Erson‐Omay, Hyo-Eun Moon, Lucy F. Stead, Joanna J. Phillips, Rachael A. Vaubel, Peter S. LaViolette, Nader Sanai, Anna Golebiewska, Kevin J. Anderson, Mathilde C.M. Kouwenhoven, Marta Padovan, Roel G.W. Verhaak, Marion Smits, Spyridon Bakas, Beth Hermes, Simone P. Niclou, Gaetano Finocchiaro, Pieter Wesseling, Jill S. Barnholtz‐Sloan, Colin Watts, MacLean P. Nasrallah, Cihat Karadağ, Anna Lasorella, Kerryn T. Westcott, Ana Valeria Castro, Samirkumar B. Amin, Sun Ha Paek, David M. Ashley, Carol Elliott, Erica Shen, Kenneth Aldape, Kevin C. Johnson, Bart A. Westerman, Kay Li, Gelareh Mohammed Zadeh, Tamrin Chowdhury, Laila Poisson, C. Mircea S. Tesileanu, Antonio Iavarone, Erwin G. Van Meir, Houtan Noushmehr, Daniel Jay Brat, Sushant Puri, Youri Hoogstrate, Susan C Short, J Costello, Andrew Edward Sloan, Allison K. Lowman, Jennifer Connelly, Pranav Swaroop Gundla, Chaewon Heo, Indrani Datta, Elizabeth B. Claus, Chibo Hong, Annette M Molinaro, Do-Hyun Nam, Peter A.E. Sillevis Smitt, Shwetal Mehta, Bethany Kwan, Hoon Kim, H. K. Ng, John F. de Groot, Tathiane M. Malta, Hiromichi Suzuki, Joo Ho Lee
article en

Abstract

Astrocytomas and oligodendrogliomas are isocitrate dehydrogenase (IDH)-mutant gliomas that most commonly arise in adults under the age of 50 and exhibit variable responses to treatment1–3. To understand the genetic drivers of disease progression, here we used whole-genome and whole-exome sequencing to characterize longitudinally collected tumour specimens from 183 patients with IDH-mutant glioma. Samples were collected through the Glioma Longitudinal Analysis (GLASS) Consortium4. Most primary surgery samples were classified as grade 2 on the basis of histology (73% for astrocytomas and 93% for oligodendrogliomas). We validated known genomic markers of tumour progression, including hypermutation and homozygous deletion of CDKN2A or CDKN2B (hereafter, CDKN2A/B)5, and discovered genetic alterations that distinguish between the evolutionary trajectories of astrocytomas and those of oligodendrogliomas. Mutations in phosphatidylinositol 3-kinase (PI3K) and NOTCH1 were newly acquired in recurrent oligodendrogliomas, regardless of treatment, and were associated with an increased tumour mutational burden. In recurrent astrocytomas, however, again irrespective of treatment, acquired focal oncogene amplifications and CDKN2A/B homozygous deletions were associated with an increase in chromosomal imbalances, which converged with markers of chromosomal instability such as chromothripsis and whole-genome doubling. In both types of IDH-mutant glioma, we observed a convergence of acquired alterations, genome-wide changes and worse patient outcomes, suggesting that treatment-refractory clones were being selected. Treatment with temozolomide was associated with the mutational signatures SBS11 and SBS119 in both tumour types, whereas the radiotherapy-associated ID8 signature increased in astrocytomas specifically. We show that the genomes of oligodendrogliomas and astrocytomas adapt to the selective pressures of tumour progression and treatment in distinct ways, suggesting that oligodendrogliomas and astrocytomas differ in their responses to treatment-induced DNA damage. Longitudinal genomic analyses in patients with astrocytoma or oligodendrioglioma suggest that these two types of tumour differ in the mechanisms by which they become resistant to treatment, with astrocytomas accumulating copy-number alterations and chromosomal instability markers but oligodendrogliomas acquiring new driver mutations.

Nature
Northwestern University (US), Brigham and Women's Hospital (US), Translational Genomics Research Institute (US), National Institutes of Health (US), University of Leeds (GB), Barrow Neurological Institute (US), St. Joseph's Hospital and Medical Center (US), Mayo Clinic (US), Universidade de Ribeirão Preto (BR), University Medical Center Groningen (NL), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Seoul National University (KR), University of Miami (US), Henry Ford Health System (US), Oregon Health & Science University (US), University of Groningen (NL), Duke University (US), Universidade de São Paulo (BR), University of California, San Francisco (US), Baylor College of Medicine (US), Wright State University (US), University of Zurich (CH), Medical College of Wisconsin (US), St James's University Hospital (GB), Erasmus MC (NL), Samsung Medical Center (KR), Walton Centre (GB), Seoul National University Hospital (KR), Henry Ford Hospital (US), University of Alabama at Birmingham (US), Yale University (US), University of California San Diego (US), National Cancer Centre Japan (JP), Düsseldorf University Hospital (DE), University Hospital of Zurich (CH), Luxembourg Institute of Health (LU), Prince of Wales Hospital (CN), Jackson Laboratory (US), Dana-Farber Cancer Institute (US), Essen University Hospital (DE), Advanced Institute of Convergence Technology (KR), Duke Medical Center (US), Princess Máxima Center (NL), IRCCS Ospedale San Raffaele (IT), Dana-Farber/Harvard Cancer Center (US), Cancer Research UK Clinical Trials Unit (GB), National Cancer Institute (US), Amsterdam University Medical Centers (NL), Clinics Hospital of Ribeirão Preto (BR), Sylvester Comprehensive Cancer Center (US), Olivia Newton-John Cancer Wellness & Research Centre (AU), Abramson Cancer Center (US), Indiana University School of Medicine, The Jackson Laboratory for Genomic Medicine (US), Heinrich Heine University Düsseldorf (DE), University of Colorado Anschutz Medical Campus (US), University of Duisburg-Essen (DE), UConn Health (US), Medical University of Vienna (AT), University of Pennsylvania (US), University of Birmingham (GB), Sungkyunkwan University (KR), Erasmus University Rotterdam (NL)
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Glioma Diagnosis and Treatment
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