Cancer discovery最新文献

{"title":"PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State.","authors":"Shane T Killarney, Gabriel Mesa, Rachel Washart, Benjamin Mayro, Kerry Dillon, Suzanne E Wardell, Madeline Newlin, Min Lu, Areej Abu Rmaileh, Nicky Liu, Donald P McDonnell, Ann Marie Pendergast, Kris C Wood","doi":"10.1158/2159-8290.CD-24-0928","DOIUrl":"10.1158/2159-8290.CD-24-0928","url":null,"abstract":"<p><p>Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. In this study, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ∼800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Coessentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts. Significance: This work identifies PKN2 as a core member of the Hippo signaling pathway, and its inhibition blocks YAP/TAZ-driven tumorigenesis. Furthermore, this study discovers PKN2-TAZ as arguably the most selective dependency of mesenchymal-like cancers and supports specific inhibition of PKN2 as a provocative strategy to overcome drug resistance in diverse cancer contexts. See related commentary by Shen and Tan, p. 458.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"595-615"},"PeriodicalIF":29.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell eQTL mapping reveals cell subtype-specific genetic control and mechanism in malignant transformation of colorectal cancer","authors":"Can Chen, Yimin Cai, Wenlong Hu, Kai Tan, Zequn Lu, Xuanyu Zhu, Ziying Liu, Chunyi He, Guangping Xu, Ruizhe Zhang, Caibo Ning, Shuheng Ruan, Jiayan Gao, Xiaojun Yang, Yongchang Wei, Xu Zhu, Xiangpan Li, Faxi Wang, Fubing Wang, Jiaoyuan Li, Meng Jin, Bin Li, Ying Zhu, Jianbo Tian, Xiaoping Miao","doi":"10.1158/2159-8290.cd-24-1561","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1561","url":null,"abstract":"Colorectal cancer (CRC) is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. Here, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular crosstalk during CRC development. Additionally, we created a CRC sc-eQTL map identifying 16,833 significant pairs across 28 cell subtypes, with over 76% of sc-eQTLs being cell-type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score (PRS) derived from sc-eQTLs substantially improved CRC risk prediction. We prioritized rs4794979 that is associated with an increased CRC risk (OR=1.11, P=2.04×10-12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts (CAFs), simultaneously induces CD8+ T cells exhaustion via LGALS9-TIM3 axis, thereby facilitating CRC development. Blocking LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit CRC progression.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"29 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538605","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 reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation","authors":"Alessio Ugolini, Alessandra De Leo, Xiaoqing Yu, Fabio Scirocchi, Xiaoxian Liu, Barbara Peixoto, Delia Scocozza, Angelica Pace, Michela Perego, Alessandro Gardini, Luca D'Angelo, James K C. Liu, Arnold B. Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A. Vogelbaum, Jose R. Conejo-Garcia, Paulo C. Rodriguez, Filippo Veglia","doi":"10.1158/2159-8290.cd-24-1056","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1056","url":null,"abstract":"Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518768","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":"GPR65 inactivation in tumor cells drives antigen-independent CAR-T cell resistance via macrophage remodeling.","authors":"Jayadev Mavuluri, Yogesh Dhungana, Lindsay L Jones, Sheetal Bhatara, Hao Shi, Xu Yang, Song-Eun Lim, Noemi Reyes, Hongbo Chi, Jiyang Yu, Terrence L Geiger","doi":"10.1158/2159-8290.CD-24-0841","DOIUrl":"10.1158/2159-8290.CD-24-0841","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapies, while promising for CD19+ hematological malignancies, often face setbacks due to relapses. Our research identifies GPR65 as a tumor-specific determinant affecting the efficacy of CAR-T cell therapy. In human patients and an immune-competent mouse model of B-cell acute lymphoblastic leukemia (B-ALL), low GPR65 expression correlates with resistance to CD19+ CAR-T treatment. GPR65 knockout (GPR65 KO) tumors in mice similarly exhibit resistance. Through single-cell network analyses, we discovered that GPR65 deficiency reshapes tumor interactions with host macrophages by increasing tumor VEGFA levels, leading to macrophage expansion and preferential M2 polarization. Depleting host macrophages or by deletion of VEGFA in GPR65 KO tumors, restores CAR-T cell therapy responsiveness. Moreover, combining anti-VEGFA therapy with CAR-T cell treatment significantly prolongs the survival of mice bearing GPR65 KO tumors. These findings emphasize the profound impact of tumor gene expression on the tumor microenvironment and subsequent CAR-T cell therapy outcomes.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490861","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":"A Roadmap to Precision Immunotherapy for Early-Stage Non-Small Cell Lung Cancer.","authors":"Alessandra Vaccaro, Zahraa Rahal, Humam Kadara, Tina Cascone","doi":"10.1158/2159-8290.CD-25-0262","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-25-0262","url":null,"abstract":"<p><p>Immunotherapy has revolutionized the treatment of early-stage non-small cell lung cancer; yet many patients fail to achieve long-lasting benefit, partially because of incomplete or inconsistent biomarker predictions. Integrative multiomics, combining tumor-intrinsic, immune microenvironment, and systemic factors, offer a more comprehensive framework for precision immunotherapy, enabling improved patient stratification, treatment selection and outcomes.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1-OF6"},"PeriodicalIF":29.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490860","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":"Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma.","authors":"Miya B Hugaboom, Lena V Wirth, Kelly Street, Neil Ruthen, Opeyemi A Jegede, Nicholas R Schindler, Valisha Shah, Jacob P Zaemes, Nourhan El Ahmar, Sayed Matar, Varunika Savla, Toni K Choueiri, Thomas Denize, Destiny J West, David F McDermott, Elizabeth R Plimack, Jeffrey A Sosman, Naomi B Haas, Mark N Stein, Robert Alter, Mehmet A Bilen, Michael E Hurwitz, Hans Hammers, Sabina Signoretti, Michael B Atkins, Catherine J Wu, David A Braun","doi":"10.1158/2159-8290.CD-24-0991","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0991","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) targeting the PD-1 pathway have transformed treatment of advanced renal cell carcinoma (RCC), but mechanisms underlying therapeutic response remain largely unknown. Herein, we perform transcriptomic analysis on RCC biospecimens from 102 patients enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309) to investigate determinants of response to anti-PD1 monotherapy. Through bulk analysis, we identify an enrichment of genes associated with tertiary lymphoid structures (TLS) in responding patients. Using single-cell transcriptomics and external cohort validation, we identify a population of tissue-resident (ZNF683+ SLAMF7+) exhausted CD8+ T cells enriched in patients with poor clinical outcomes. Integrating these findings, we find tumors with high TLS and low tissue-resident exhausted CD8+ T cells have superior clinical outcomes with nivolumab. Altogether, these analyses contribute to a growing understanding of how the tumor microenvironment drives ICI- resistance and propose possible therapeutic targets to rationally overcome resistance to anti-PD1 monotherapy.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482121","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":"Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy","authors":"Christopher A. Febres-Aldana, Morana Vojnic, Igor Odintsov, Tom Zhang, Ryan Cheng, Catherine Z. Beach, Daniel Lu, Marissa S. Mattar, Andrea M. Gazzo, Leo Gili, Manju Harshan, Ali Ameri, Stephen Machnicki, Xiuying Xiao, William W. Lockwood, Xiao-yan Zhou, Qianlan Yao, Alexander Drilon, Natasha Rekhtman, Nameeta Shah, Anqi Li, Zebing Liu, Soo-Ryum Yang, Monika A. Davare, Marc Ladanyi, Romel Somwar","doi":"10.1158/2159-8290.cd-24-0417","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0417","url":null,"abstract":"MET fusions (MET-Fs) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA-seq plus 11,255 RNA-seq) uncovered two forms of MET-F pathobiology. The first group featured 5’ partners with homodimerization domains fused in-frame with MET-tyrosine kinase domain (TKD), primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in pre-clinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with RTK co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET-TKI sensitivity are determined by structural topology and pathogenomic context.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"53 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443172","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":"High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non–Small Cell Lung Cancer in Patients","authors":"Ling Cai, Nia G. Hammond, Alpaslan Tasdogan, Massar Alsamraae, Chendong Yang, Robert B. Cameron, Peiran Quan, Ashley Solmonson, Wen Gu, Panayotis Pachnis, Mayher Kaur, Brianna K. Chang, Qin Zhou, Christopher T. Hensley, Quyen N. Do, Luiza Martins Nascentes Melo, Jessalyn M. Ubellacker, Akash Kaushik, Maia G. Clare, Isabel N. Alcazar, Katarzyna Kurylowicz, Joseph D. Marcuccilli, Gabriele Allies, Andrea Kutritz, Joachim Klode, Vijayashree Ramesh, Thomas J. Rogers, Aparna D. Rao, Hannah E. Crentsil, Hong Li, Fang Brister, Phyllis McDaniel, Xiaohong Xu, Bret M. Evers, Lauren G. Zacharias, Jessica Sudderth, Jian Xu, Thomas P. Mathews, Dwight Oliver, John D. Minna, John Waters, Sean J. Morrison, Kemp H. Kernstine, Brandon Faubert, Ralph J. DeBerardinis","doi":"10.1158/2159-8290.cd-23-1319","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1319","url":null,"abstract":"In patients with non–small cell lung cancer (NSCLC), the relationship between tumor metabolism and clinical outcomes is unknown. Here, 13C-labeled nutrients were intraoperatively infused into more than 90 patients with surgically resectable pulmonary lesions, and metabolic properties of resected tumors were correlated with survival. In NSCLCs infused with 13C-glucose, high 13C enrichment in tricarboxylic acid (TCA) cycle intermediates conferred a HR of 3.8 for early death, typically with metastasis. To test whether these features reflect requirements for metastasis, we generated patient-derived xenografts that spontaneously metastasize to multiple organs. Treatment with an electron transport chain (ETC) inhibitor reduced glucose-derived TCA cycle labeling but did not suppress subcutaneous tumor growth. However, ETC blockade reduced the abundance of circulating cancer cells and suppressed xenograft metastatic burden in distant organs. Our data demonstrate that isotope labeling can identify metabolic properties associated with metastasis in patients and that blocking the ETC suppresses metastasis in mice. Significance: Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"80 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435288","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":"Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small Molecule Reactivator.","authors":"Anna M Puzio-Kuter, Lizhong Xu, Mary Kate McBrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky","doi":"10.1158/2159-8290.CD-24-1421","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1421","url":null,"abstract":"<p><p>Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. Here, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing anti-proliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild type p53 program. These compounds demonstrate potent anti-tumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational Phase 2 clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405675","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 Germline and Somatic Origins of Prostate Cancer Heterogeneity.","authors":"Takafumi N Yamaguchi, Kathleen E Houlahan, Helen Zhu, Natalie Kurganovs, Julie Livingstone, Natalie S Fox, Jiapei Yuan, Jocelyn Sietsma Penington, Chol-Hee Jung, Tommer Schwarz, Weerachai Jaratlerdsiri, Job van Riet, Peter Georgeson, Stefano Mangiola, Kodi Taraszka, Robert Lesurf, Jue Jiang, Ken Chow, Lawrence E Heisler, Yu-Jia Shiah, Susmita G Ramanand, Michael J Clarkson, Anne Nguyen, Shadrielle Melijah G Espiritu, Ryan Stuchbery, Richard Jovelin, Vincent Huang, Connor Bell, Edward O'Connor, Patrick J McCoy, Christopher M Lalansingh, Marek Cmero, Adriana Salcedo, Eva K F Chan, Lydia Y Liu, Phillip D Stricker, Vinayak Bhandari, Riana M S Bornman, Dorota Hs Sendorek, Andrew Lonie, Stephenie D Prokopec, Michael Fraser, Justin S Peters, Adrien Foucal, Shingai B A Mutambirwa, Lachlan Mcintosh, Michèle Orain, Matthew Wakefield, Valérie Picard, Daniel J Park, Hélène Hovington, Michael Kerger, Alain Bergeron, Veronica Sabelnykova, Ji-Heui Seo, Mark M Pomerantz, Noah Zaitlen, Sebastian M Waszak, Alexander Gusev, Louis Lacombe, Yves Fradet, Andrew Ryan, Amar U Kishan, Martijn P Lolkema, Joachim Weischenfeldt, Bernard Têtu, Anthony J Costello, Vanessa M Hayes, Rayjean J Hung, Housheng H He, John D McPherson, Bogdan Pasaniuc, Theodorus van der Kwast, Anthony T Papenfuss, Matthew L Freedman, Bernard J Pope, Robert G Bristow, Ram S Mani, Niall M Corcoran, Jüri Reimand, Christopher M Hovens, Paul C Boutros","doi":"10.1158/2159-8290.CD-23-0882","DOIUrl":"10.1158/2159-8290.CD-23-0882","url":null,"abstract":"<p><p>Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common pre-malignant field, influenced by germline genomic context and stochastic mutation-timing.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405678","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}