Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations inTP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

Type: Exome Sequencing
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 12 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001000714	None		102

Publications	Citations
Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJM, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF. Science 343: 2014 189-193	836
Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmström A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers ML, Saito N, Aburatani H, Mukasa A, Berger MS, Söderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF. Acta Neuropathol 129: 2015 597-607	103
DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJA, Smirnov IV, Reis GF, Phillips JJ, Barnes MJ, Idbaih A, Alentorn A, Kloezeman JJ, Lamfers MLM, Bollen AW, Taylor BS, Molinaro AM, Olshen AB, Chang SM, Song JS, Costello JF. Cancer Cell 28: 2015 307-317	162
Clonal evolution of glioblastoma under therapy. Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, Abate F, Liu Z, Elliott O, Shin YJ, Lee JK, Lee IH, Park WY, Eoli M, Blumberg AJ, Lasorella A, Nam DH, Finocchiaro G, Iavarone A, Rabadan R. Nat Genet 48: 2016 768-776	420
Between-region genetic divergence reflects the mode and tempo of tumor evolution. Sun R, Hu Z, Sottoriva A, Graham TA, Harpak A, Ma Z, Fischer JM, Shibata D, Curtis C. Nat Genet 49: 2017 1015-1024	78
Comprehensive Analysis of Hypermutation in Human Cancer. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP, Zahurancik WJ, Suo Z, Lipman T, Wimmer K, Kratz CP, Bowers DC, Laetsch TW, Dunn GP, Johanns TM, Grimmer MR, Smirnov IV, Larouche V, Samuel D, Bronsema A, Osborn M, Stearns D, Raman P, Cole KA, Storm PB, Yalon M, Opocher E, Mason G, Thomas GA, Sabel M, George B, Ziegler DS, Lindhorst S, Issai VM, Constantini S, Toledano H, Elhasid R, Farah R, Dvir R, Dirks P, Huang A, Galati MA, Chung J, Ramaswamy V, Irwin MS, Aronson M, Durno C, Taylor MD, Rechavi G, Maris JM, Bouffet E, Hawkins C, Costello JF, Meyn MS, Pursell ZF, Malkin D, Tabori U, Shlien A. Cell 171: 2017 1042-1056.e10	406
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Caswell-Jin JL, McNamara K, Reiter JG, Sun R, Hu Z, Ma Z, Ding J, Suarez CJ, Tilk S, Raghavendra A, Forte V, Chin SF, Bardwell H, Provenzano E, Caldas C, Lang J, West R, Tripathy D, Press MF, Curtis C. Nat Commun 10: 2019 657	31
MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence. Mathur R, Zhang Y, Grimmer MR, Hong C, Zhang M, Bollam S, Petrecca K, Clarke J, Berger MS, Phillips JJ, Oberheim-Bush NA, Molinaro AM, Chang SM, Costello JF. Neuro Oncol 22: 2020 1580-1590	48
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells. Chung J, Maruvka YE, Sudhaman S, Kelly J, Haradhvala NJ, Bianchi V, Edwards M, Forster VJ, Nunes NM, Galati MA, Komosa M, Deshmukh S, Cabric V, Davidson S, Zatzman M, Light N, Hayes R, Brunga L, Anderson ND, Ho B, Hodel KP, Siddaway R, Morrissy AS, Bowers DC, Larouche V, Bronsema A, Osborn M, Cole KA, Opocher E, Mason G, Thomas GA, George B, Ziegler DS, Lindhorst S, Vanan M, Yalon-Oren M, Reddy AT, Massimino M, Tomboc P, Van Damme A, Lossos A, Durno C, Aronson M, Morgenstern DA, Bouffet E, Huang A, Taylor MD, Villani A, Malkin D, Hawkins CE, Pursell ZF, Shlien A, Kunkel TA, Getz G, Tabori U. Cancer Discov 11: 2021 1176-1191	37
Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition. Campbell BB, Galati MA, Stone SC, Riemenschneider AN, Edwards M, Sudhaman S, Siddaway R, Komosa M, Nunes NM, Nobre L, Morrissy AS, Zatzman M, Zapotocky M, Joksimovic L, Kalimuthu SN, Samuel D, Mason G, Bouffet E, Morgenstern DA, Aronson M, Durno C, Malkin D, Maris JM, Taylor MD, Shlien A, Pugh TJ, Ohashi PS, Hawkins CE, Tabori U. Cancer Discov 11: 2021 1454-1467	21
Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Garofano L, Migliozzi S, Oh YT, D'Angelo F, Najac RD, Ko A, Frangaj B, Caruso FP, Yu K, Yuan J, Zhao W, Di Stefano AL, Bielle F, Jiang T, Sims P, Suvà ML, Tang F, Su XD, Ceccarelli M, Sanson M, Lasorella A, Iavarone A. Nat Cancer 2: 2021 141-156	146
Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma. Nam Y, Koo H, Yang Y, Shin S, Zhu Z, Kim D, Cho HJ, Mu Q, Choi SW, Sa JK, Seo YJ, Kim Y, Lee K, Oh JW, Kwon YJ, Park WY, Kong DS, Seol HJ, Lee JI, Park CK, Lee HW, Yoon Y, Wang J. Genome Med 15: 2023 16	6