Cancer discovery最新文献

{"title":"Epigenetic and transcriptional programs define osteosarcoma subtypes and establish targetable vulnerabilities.","authors":"Eunice Lopez-Fuentes,Andrew S Clugston,Alex G Lee,Leanne C Sayles,Natalie Sorensen,María V Pons Ventura,Stanley G Leung,Truc Dinh,Marcus R Breese,E Alejandro Sweet-Cordero","doi":"10.1158/2159-8290.cd-25-0237","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0237","url":null,"abstract":"Osteosarcoma is a genomically complex tumor characterized by widespread structural rearrangements. This complexity has limited development of therapeutic strategies informed by molecular mechanisms of oncogenesis. We hypothesized that epigenetic mechanisms could drive distinct subtypes of osteosarcoma. Through analysis of chromatin accessibility, we identified an \"early osteoblast-derived\" (EOD) cell state characterized by upregulation of transcription factors associated with early bone development, and a \"late osteoblast-derived\" state (LOD), characterized by upregulation of genes involved in late bone development. We then defined core regulatory circuitries governing the underlying gene expression programs in these two cell states. Multiomic single-cell analysis indicates that these cell states co-exist in a single tumor. Finally, using a panel of patient-derived xenograft models, we identified differential drug responses dependent on these cellular states. These findings create opportunities for developing new combination therapy strategies for osteosarcoma treatment and underscore the value of defining epigenetic subtypes in highly genomically complex cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"76 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of chromosomal instability by EZH2 methyltransferase.","authors":"Yang Bai,Albert S Agustinus,Shira Yomtoubian,Cem Meydan,Dylan R McNally,Liron Yoffe,Melissa J Hubisz,Marvel Tranquille,Sneha Pramod,Christy Hong,Magdalena L Plasilova,Aakanksha R Kapoor,Arshdeep Singh,Henry Withers,Lukas E Dow,Ashley M Laughney,Bhavneet Bhinder,Olivier Elemento,Ari M Melnick,Samuel F Bakhoum,Vivek Mittal","doi":"10.1158/2159-8290.cd-25-0947","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0947","url":null,"abstract":"Chromosomal instability (CIN) and epigenetic reprogramming are central drivers of breast cancer progression, yet the mechanisms connecting them remain elusive. We uncover a direct role of EZH2 histone methyltransferase in promoting CIN in triple-negative breast cancer (TNBC). Across breast cancers, EZH2 expression correlates with copy number alterations, and its catalytic activity is associated with increased CIN in metastasis-initiating cells. Pharmacological EZH2 inhibition suppressed CIN, revealing an unexpected vulnerability. Integrated chromatin and transcriptome profiling identified Tankyrase (TNKS), a poly(ADP-ribose) polymerase, as a direct transcriptional target of EZH2. Mechanistically, EZH2-mediated TNKS suppression disrupts CPAP (centrosomal P4.1-associated protein), driving centrosome overduplication, multipolar mitosis and exacerbated CIN. In vivo, CIN suppression is a critical mechanism underlying the anti-metastatic effects of EZH2 inhibition. These findings delineate a previously unrecognized epigenetic mechanism governing CIN and establish EZH2 inhibitors as the first therapeutic agents capable of directly suppressing CIN, underscoring the need for trials with metastasis-focused endpoints.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"22 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.","authors":"Divij Verma, Rachel Zeig-Owens, David G Goldfarb, Leah Kravets, Kith Pradhan, Bradley Rockwell, Srabani Sahu, Susheian Kelly, Orsi Giricz, Sakshi Jasra, Yiyu Zou, Colette Prophete, Lidiane S Torres, Srinivas Aluri, Samarpana Chakraborty, Rajni Kumari, Shanisha Gordon-Mitchell, Jingli Wang, Alexander J Silver, Taylor M South, Sarah D Olmstead, Charles B Hall, Simone Sidoli, Ryan Bender, Ola Landgren, Lee M Greenberger, Amittha Wickrema, Advaitha Madireddy, Aditi Shastri, Eric M Pietras, Lindsay M LaFave, Anna Nolan, Mitchell D Cohen, Michael R Savona, Ulrich Steidl, David J Prezant, Amit Verma","doi":"10.1158/2159-8290.CD-24-1590","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1590","url":null,"abstract":"<p><p>Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first-responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared to two sets of control cohorts after controlling for age, race, and sex. Younger exposed first-responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%, OR=5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cell while expanding Tet2-mutant CH clones in mice. Inflammation sensor, IL1RAP, was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in-vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":33.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional mapping of epigenomic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes","authors":"Yuning J. Tang, Haiqing Xu, Nicholas W. Hughes, Paloma Ruiz, Samuel H. Kim, Emily G. Shuldiner, Steven S. Lopez, Jess D. Hebert, Saswati Karmakar, Laura Andrejka, Deniz Nesli Dolcen, Gabor Boross, Pauline Chu, Christian A. Kunder, Colin Detrick, Sarah E. Pierce, Emily L. Ashkin, William J. Greenleaf, Anne K. Voss, Tim Thomas, Matt van de Rijn, Dmitri A. Petrov, Monte M. Winslow","doi":"10.1158/2159-8290.cd-24-1565","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1565","url":null,"abstract":"Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a novel high-throughput in vivo method to perform iterative functional screens of &amp;gt;250 epigenomic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenomic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, impact chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"99 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial metabolic pathways guide response to immune checkpoint blockade therapy.","authors":"Iris L Mimpen,Thomas W Battaglia,Miguel Parra Martinez,Catherine Toner-Bartelds,Laurien J Zeverijn,Birgit S Geurts,Karlijn Verkerk,Louisa R Hoes,Allard W J van Renterghem,Michael Noe,Ingrid Hofland,Annegien Broeks,Vincent van der Noort,Edwin C A Stigter,Can M C Gulersonmez,Boudewijn M T Burgering,Merel van Gogh,Marcel R de Zoete,Hans Gelderblom,Krijn K Dijkstra,Lodewyk F A Wessels,Emile E Voest","doi":"10.1158/2159-8290.cd-24-1669","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1669","url":null,"abstract":"Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"41 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EML4-ALK variant-specific genetic interactions shape lung tumorigenesis","authors":"Alberto Diaz-Jimenez, Emily G. Shuldiner, Kalman Somogyi, Karen Shih, Oscar Gonzalez-Velasco, Mulham Najajreh, Stewart Kim, Filiz Akkas, Christopher W. Murray, Laura Andrejka, Min K. Tsai, Benedikt Brors, Ilse Hofmann, Smruthy Sivakumar, Saumya D. Sisoudiya, Ethan S. Sokol, Hongchen Cai, Dmitri A. Petrov, Monte M. Winslow, Rocio Sotillo","doi":"10.1158/2159-8290.cd-24-1417","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1417","url":null,"abstract":"Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"11 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Prospective Validation of a Cell-free DNA-based Model for the Early Detection of Pancreatic Cancer","authors":"Xiuchao Wang, Hongwei Wang, Meng Zhang, Huikai Li, Yang Liu, HanFei Huang, Jinlong Pei, Jing Huang, Fenglin Zang, Yanhui Zhang, Xingyun Chen, Song Gao, Tiansuo Zhao, Jian Wang, Weidong Ma, Yuexiang Liang, Shangheng Shi, Shuo Li, Wei Li, Tianxing Zhou, Ying Zhang, Xiaonan Cui, Zhao-Xiang Ye, Yan Sun, Li Peng, Xiao Hu, Zhitao Li, Hao Zhang, Dongqin Zhu, Shuang Chang, Jiangyan Zhang, Ruowei Yang, Hua Bao, Xue Wu, Yang Shao, Jun Yu, Chuntao Gao, Yunfeng Cui, Jihui Hao","doi":"10.1158/2159-8290.cd-25-0323","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0323","url":null,"abstract":"Pancreatic cancer (PC) remains a highly lethal malignancy due to late-stage diagnosis and limited therapeutic options. This study presents the development and validation of a non-invasive circulating cell-free DNA (cfDNA)-based model for early PC detection. In a case-control study comprising 232 PC patients and 235 healthy controls, the model demonstrated high diagnostic accuracy (AUC=0.9799 in training; 0.9622 in validation). A prospective cohort study involving 1,926 individuals with diabetes and obesity, established risk factors for PC, further assessed its clinical applicability. The model detected 75% of PC cases, including all Stage 0 patients, with a lead time of up to 298 days, significantly outperforming CA19-9. Additionally, it demonstrates potential for distinguishing high-risk from low-risk pancreatic cysts, thereby facilitating more precise risk stratification. This study highlights the potential of cfDNA-based screening as a scalable, non-invasive tool for early PC detection, warranting further large-scale clinical validation to enhance patient outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"33 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.","authors":"Marco Avolio,Simonetta M Leto,Francesco Sassi,Barbara Lupo,Elena Grassi,Irene Catalano,Eugenia R Zanella,Valentina Vurchio,Francesca Cottino,Petros K Tsantoulis,Luca Lazzari,Paolo Luraghi,Martina Ferri,Francesco Galimi,Enrico Berrino,Sara E Bellomo,Marco Viviani,Alberto Sogari,Gianluca Mauri,Federica Tosi,Federica Cruciani,Andrea Sartore-Bianchi,Salvatore Siena,Felice Borghi,Valter Torri,Elena Élez,Josep Tabernero,Maria Nieva,Clara Montagut,Noelia Tarazona,Andres Cervantes,Sabine Tejpar,Alberto Bardelli,Caterina Marchiò,Silvia Marsoni,Andrea Bertotti,Livio Trusolino","doi":"10.1158/2159-8290.cd-24-0556","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0556","url":null,"abstract":"The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC), yet benefits only about half of patients. Using patient-derived xenografts (PDXs), we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, while HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, non-genetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"50 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.","authors":"Xiaojun Yan,Wenbin Xu,Han Yao,Zhen Wu,Jingyuan Ning,Shidong Zhao,Yajing Liu,Meng Zhang,Dongkui Xu,Zhanlong Shen,Wei Gu,Donglai Wang","doi":"10.1158/2159-8290.cd-25-0649","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0649","url":null,"abstract":"Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"9 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.","authors":"Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E Weeden, Donald M Bell, Eric Joo, Vittorio Barbè, Matthew G Jones, King L Hung, Emma L Nye, Mary Green, Lucy Meader, Emma J Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal-Hanjani, Thomas Santarius, Andrea Ventura, James A R Nicoll, Delphine Boche, Howard Y Chang, Vineet Bafna, Weini Huang, Paul S Mischel, Charles Swanton, Benjamin Werner","doi":"10.1158/2159-8290.CD-24-1555","DOIUrl":"10.1158/2159-8290.CD-24-1555","url":null,"abstract":"<p><p>Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.</p><p><strong>Significance: </strong>We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1-OF18"},"PeriodicalIF":33.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}