Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-25-0965
Tao Ren, Faming Zhao, Canping Chen, Le Zhou, Ling-Yun Wu, Gordon B. Mills, Lisa M. Coussens, Zheng Xia
{"title":"scSurvival: Single-Cell Survival Analysis of Clinical Cancer Cohort Data at Cellular Resolution","authors":"Tao Ren, Faming Zhao, Canping Chen, Le Zhou, Ling-Yun Wu, Gordon B. Mills, Lisa M. Coussens, Zheng Xia","doi":"10.1158/2159-8290.cd-25-0965","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0965","url":null,"abstract":"Survival analysis is fundamental to cancer research. Advances in technology have enabled an increasing number of cohort-level cancer studies to incorporate single-cell sequencing alongside clinical survival data. However, no effective strategy currently exists for directly modeling survival outcomes from single-cell data. To address this gap, we present scSurvival, an attention-based multiple-instance Cox regression framework that models each tumor sample as an ensemble of cells to predict survival outcomes at both the patient and single-cell levels. To handle high dimensionality, sparsity, and batch effects, scSurvival integrates a variational autoencoder–based feature extraction module with generative modeling to enhance feature robustness and cross-batch generalizability. Comprehensive simulations demonstrate scSurvival’s superior performance and scalability. In melanoma and liver cancer single-cell RNA sequencing (scRNA-seq) cohorts, scSurvival accurately predicts patient outcomes and identifies the cell subpopulations most critical to survival. Overall, scSurvival enables robust prediction of patient survival while uncovering survival-associated cell subpopulations, advancing single-cell survival analysis in cancer research. Significance: Survival analysis is central to clinical oncology, yet no effective tools currently model survival outcomes directly from single-cell data. scSurvival bridges this gap by predicting patient outcomes and identifying key subpopulations from scRNA-seq with survival information, enabling scalable analyses and promoting broader adoption of cohort-level single-cell profiling in cancer research.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"29 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733657","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-25-1745
Katie M Campbell,Daniel G Chen,Zaid E Bustami,Nataly Naser Al Deen,Egmidio Medina,Cynthia R Gonzalez,Jessica Maxey,Marshall A Thompson,Sarah Samorodnitsky,Lawrence F Kuklinski,Ivan Perez Garcilazo,Ignacio Baselga-Carretero,Agustin Vega-Crespo,Jia Ming Chen,Rangasamy Elumalai,Marc Visitacion,Rob Schiemann,Lacey Padron,Cadence Chang,Alan E Zelin,Sai S Chelluri,Silvia Boffo,Kari L Kendra,Bartosz Chmielowski,Thach-Giao Truong,Nikhil I Khushalani,Frances Collichio,Alexandra P Ikeguchi,Adrienne I Victor,Kim A Margolin,Douglas B Johnson,Yuanbin Chen,Jeffrey A Sosman,Sapna P Patel,Siwen Hu-Lieskovan,James Moon,Daniel K Wells,Christine N Spencer,Shay Bellasea,Ari M Vanderwalde,Michael C Wu,Philip O Scumpia,Antoni Ribas
{"title":"Cellular neighborhoods govern antitumor T-cell infiltration following anti-CTLA-4 in melanoma with primary resistance to anti-PD-1.","authors":"Katie M Campbell,Daniel G Chen,Zaid E Bustami,Nataly Naser Al Deen,Egmidio Medina,Cynthia R Gonzalez,Jessica Maxey,Marshall A Thompson,Sarah Samorodnitsky,Lawrence F Kuklinski,Ivan Perez Garcilazo,Ignacio Baselga-Carretero,Agustin Vega-Crespo,Jia Ming Chen,Rangasamy Elumalai,Marc Visitacion,Rob Schiemann,Lacey Padron,Cadence Chang,Alan E Zelin,Sai S Chelluri,Silvia Boffo,Kari L Kendra,Bartosz Chmielowski,Thach-Giao Truong,Nikhil I Khushalani,Frances Collichio,Alexandra P Ikeguchi,Adrienne I Victor,Kim A Margolin,Douglas B Johnson,Yuanbin Chen,Jeffrey A Sosman,Sapna P Patel,Siwen Hu-Lieskovan,James Moon,Daniel K Wells,Christine N Spencer,Shay Bellasea,Ari M Vanderwalde,Michael C Wu,Philip O Scumpia,Antoni Ribas","doi":"10.1158/2159-8290.cd-25-1745","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1745","url":null,"abstract":"In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with continued anti-PD-1 with nivolumab, over ipilimumab alone. Baseline biopsies from patients responsive to combination therapy had increased transcriptomic expression of complement by myeloid cells, interferon pathways by endothelial cells, and oxidative phosphorylation and lipid metabolism by melanoma cells. Using spatial proteomics, some on-therapy biopsies from patients responding to combination therapy had networks of activated CD8 T cells nearby melanoma cells, while others had T cells and myeloid cells, reflective of different timepoints in a dynamic antitumor response. Conversely, biopsies from patients progressing on combination immunotherapy displayed impaired T-cell infiltration adjacent to plasma cells. Our results define cellular neighborhoods and transcriptomes in melanoma biopsies when reversing resistance to anti-PD-1 with the addition of anti-CTLA4, and plasma cell sheets in non-responding biopsies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"49 6 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731660","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-nw2026-0043
{"title":"Direct Immunotherapy Injection Shrinks Oral Precancers.","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0043","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0043","url":null,"abstract":"In a phase I clinical trial, patients with oral precancers who received immunotherapy injected directly into their lesions experienced tumor shrinkage and no dose-limiting toxicities. The findings suggest that immunotherapy could play a role in cancer prevention.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"46 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731254","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-25-1119
Jimin Min, Lisa Schweizer, Gijs Zonderland, Benson Chellakkan Selvanesan, Julie H. Thomsen, Lukas Oldenburg, Seong-Woo Bae, Bongjun Kim, Sharia D. Hernandez, Gabriela Jez, Vincent Bernard, Benjamin J. Swanson, Kelsey A. Klute, Huamin Wang, Thomas C. Caffrey, Paul M. Grandgenett, Michael A. Hollingsworth, Ishani Ummat, Maximilian T. Strauss, Andreas Mund, Anirban Maitra
{"title":"AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors","authors":"Jimin Min, Lisa Schweizer, Gijs Zonderland, Benson Chellakkan Selvanesan, Julie H. Thomsen, Lukas Oldenburg, Seong-Woo Bae, Bongjun Kim, Sharia D. Hernandez, Gabriela Jez, Vincent Bernard, Benjamin J. Swanson, Kelsey A. Klute, Huamin Wang, Thomas C. Caffrey, Paul M. Grandgenett, Michael A. Hollingsworth, Ishani Ummat, Maximilian T. Strauss, Andreas Mund, Anirban Maitra","doi":"10.1158/2159-8290.cd-25-1119","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1119","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) evolves through precursors, yet the protein programs governing early progression remain poorly defined. We applied Deep Visual Proteomics - integrating computational pathology, laser microdissection, and mass spectrometry - to profile normal ducts, acinar-to-ductal metaplasia (ADM), low- and high-grade pancreatic intraepithelial neoplasia (PanIN), and invasive carcinoma from organ donors and patients with PDAC. Quantifying 9,181 proteins from ~100 cells per region, we uncovered a molecular field effect in histologically normal ducts and proteomic divergence of low-grade PanINs by cancer context. We identified four stage-associated molecular programs. Stress adaptation and immune engagement emerged early in cancer-associated normal ducts. Metabolic reprogramming initiated in normal ducts and intensified across PanIN progression. Mitochondrial remodeling became prominent in high-grade PanINs before invasion. Mass spectrometry detected KRAS hotspot mutant peptides within incidental precursor lesions from cancer-free individuals. These findings demonstrate that molecular reprogramming precedes histological transformation, creating opportunities for earlier detection of lethal cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"263 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147733659","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}
Cancer discoveryPub Date : 2026-04-21DOI: 10.1158/2159-8290.cd-26-0003
Julian Blagg,Philippe Riou,Alexia Hervieu,Eleonora Piumatti,Maria T Rodriguez-Plata,Paolo Battuello,Adam Peall,Vito Amodio,Pietro Paolo Vitiello,Daniel J H Nightingale,Ruzica Bago,Paige Tongue,Tessa Slater,Kalpesh Parmar,Pradip Patel,Javier Rodríguez González,David E Clark,Gareth W Langley,Charles Nichols,Alba Guarne,Paul C M Winship,Matthew Baker,Martin Drysdale,Giovanni Germano,Alberto Bardelli
{"title":"Pharmacological inhibition of PMS2 induces MMR deficiency and response to immune checkpoint blockade.","authors":"Julian Blagg,Philippe Riou,Alexia Hervieu,Eleonora Piumatti,Maria T Rodriguez-Plata,Paolo Battuello,Adam Peall,Vito Amodio,Pietro Paolo Vitiello,Daniel J H Nightingale,Ruzica Bago,Paige Tongue,Tessa Slater,Kalpesh Parmar,Pradip Patel,Javier Rodríguez González,David E Clark,Gareth W Langley,Charles Nichols,Alba Guarne,Paul C M Winship,Matthew Baker,Martin Drysdale,Giovanni Germano,Alberto Bardelli","doi":"10.1158/2159-8290.cd-26-0003","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-26-0003","url":null,"abstract":"DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacological blockade of MMR could broaden the patient population eligible for immunotherapy. Here we reveal MMR protein PMS2 as a druggable target and describe the discovery and characterisation of first-in-class small molecule MMR pathway modulator NP1867. In vitro treatment of murine cancer cells abrogates MMR function and elicits an MMR-d genotype including increased TMB, MMR-d mutational signatures, and MSI-High (MSI- H) status. Inoculation of syngeneic immunocompetent mice with cancer cells pretreated with NP1867 leads to CPI sensitivity, tumour growth delay, and complete responses. For the first time, we demonstrate pharmacological targeting of MMR to proactively rewire the tumour-host relationship for therapeutic purposes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"263 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731655","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}
Cancer discoveryPub Date : 2026-04-20DOI: 10.1158/2159-8290.cd-25-0470
Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L. Wu, Mariana C.S. Mancini, Burcu Karadal-Ferrena, Sofia G. Dimitriadoy, Michael Cross, Anna H. Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M. Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E. LeBoeuf, Ting Chen, Cynthia A. Loomis, Ruth Kulicke, Fred P. Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J. Tsay, Fernando Moreira Simabuco, Charles M. Rudin, Andre L. Moreira, Kamal M. Khanna, Harvey I. Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B. Koralov, Thales Papagiannakopoulos
{"title":"LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1 -Mutant Lung Cancer","authors":"Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L. Wu, Mariana C.S. Mancini, Burcu Karadal-Ferrena, Sofia G. Dimitriadoy, Michael Cross, Anna H. Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M. Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E. LeBoeuf, Ting Chen, Cynthia A. Loomis, Ruth Kulicke, Fred P. Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J. Tsay, Fernando Moreira Simabuco, Charles M. Rudin, Andre L. Moreira, Kamal M. Khanna, Harvey I. Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B. Koralov, Thales Papagiannakopoulos","doi":"10.1158/2159-8290.cd-25-0470","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0470","url":null,"abstract":"LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell–autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1–LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression. Significance: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"10 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725842","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}
Cancer discoveryPub Date : 2026-04-20DOI: 10.1158/2159-8290.cd-25-2065
Danh-Tai Hoang, Tian-Gen Chang, Cristina R. Ferrone, Ze’ev A. Ronai, Eytan Ruppin
{"title":"AI-Driven Pathology and Blood-Based Biomarkers: A Golden Opportunity to Democratize Precision Oncology","authors":"Danh-Tai Hoang, Tian-Gen Chang, Cristina R. Ferrone, Ze’ev A. Ronai, Eytan Ruppin","doi":"10.1158/2159-8290.cd-25-2065","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-2065","url":null,"abstract":"Summary: Advancing global health equity requires a paradigm shift in precision oncology, which currently remains inaccessible to most patients worldwide because of the high cost and long turnaround time of sequencing-based biomarkers. Recent developments in artificial intelligence inference from routine histopathology slides and blood tests are now enabling rapid cost-effective prediction of survival of patients with cancer and treatment response in both developed and under-resourced regions globally.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"142 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725840","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}
Cancer discoveryPub Date : 2026-04-20DOI: 10.1158/2159-8290.cd-26-0410
Daniel Leongamornlert, Joe Lee, Aleksandra E. Kamizela, Ken To, Daniel Myers, Nicholas Williams, Kudzai Nyamondo, Xin Wang, Jing Guo, Ruchira K. Dissanayake, Jane Price, Amer J. Durrani, Jonathan Lambert, Michael Spencer Chapman, John E. Pimanda, E Joanna Baxter, Anthony R. Green, Anna L. Godfrey, Jyoti Nangalia
{"title":"Genomic evolution and natural history of myeloproliferative neoplasms on therapy","authors":"Daniel Leongamornlert, Joe Lee, Aleksandra E. Kamizela, Ken To, Daniel Myers, Nicholas Williams, Kudzai Nyamondo, Xin Wang, Jing Guo, Ruchira K. Dissanayake, Jane Price, Amer J. Durrani, Jonathan Lambert, Michael Spencer Chapman, John E. Pimanda, E Joanna Baxter, Anthony R. Green, Anna L. Godfrey, Jyoti Nangalia","doi":"10.1158/2159-8290.cd-26-0410","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-26-0410","url":null,"abstract":"Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725841","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}
Cancer discoveryPub Date : 2026-04-19DOI: 10.1158/2159-8290.cd-25-0231
Samuel W Brady,Michael A Arnold,Mingjuan Wang,Ramzi Alsallaq,Li Dong,Mohammad Aslam Khan,Wentao Yang,Kayla L Stratton,Wei Liu,Yan Chen,Emily Plyler,Jacob A Steele,Brent B Powers,David Rosenfeld,Michael N Edmonson,Yuan Feng,Nadezhda V Terekhanova,Kohei Hagiwara,Sasi Arunachalam,Heather L Mulder,Deo Kumar Srivastava,Michael Rusch,Vikki G Nolan,Aaron McDonald,Yadav Sapkota,Maria M Gramatges,Lucie M Turcotte,Cindy Im,Rebecca M Howell,John Easton,Xiaotu Ma,Zhaoming Wang,Wendy M Leisenring,Miriam Conces,Joseph P Neglia,Yutaka Yasui,Smita Bhatia,David W Ellison,Jinghui Zhang,Gregory T Armstrong
{"title":"Therapy-related mutational signatures in subsequent neoplasms among survivors of childhood cancer.","authors":"Samuel W Brady,Michael A Arnold,Mingjuan Wang,Ramzi Alsallaq,Li Dong,Mohammad Aslam Khan,Wentao Yang,Kayla L Stratton,Wei Liu,Yan Chen,Emily Plyler,Jacob A Steele,Brent B Powers,David Rosenfeld,Michael N Edmonson,Yuan Feng,Nadezhda V Terekhanova,Kohei Hagiwara,Sasi Arunachalam,Heather L Mulder,Deo Kumar Srivastava,Michael Rusch,Vikki G Nolan,Aaron McDonald,Yadav Sapkota,Maria M Gramatges,Lucie M Turcotte,Cindy Im,Rebecca M Howell,John Easton,Xiaotu Ma,Zhaoming Wang,Wendy M Leisenring,Miriam Conces,Joseph P Neglia,Yutaka Yasui,Smita Bhatia,David W Ellison,Jinghui Zhang,Gregory T Armstrong","doi":"10.1158/2159-8290.cd-25-0231","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0231","url":null,"abstract":"Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared to de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated \"flat\" signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat COSMIC signatures. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multi-sample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"23 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719476","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}
Cancer discoveryPub Date : 2026-04-19DOI: 10.1158/2159-8290.cd-25-2318
Monte M Winslow,Mohamed A Ahmed,Christine D Berg,James R M Black,Julian Downward,Ramaswamy Govindan,Roy S Herbst,John V Heymach,Elizabeth M Jaffee,Norbert Kraut,Miriam Merad,Matthew Meyerson,Tej Pandya,Katerina Politi,Arati V Rao,Charles M Rudin,Jean Charles Soria,Yuning J Tang,Kwok-Kin Wong,Timothy A Yap,Charles Swanton
{"title":"A Roadmap to Transform Lung Cancer Outcomes: Priorities in Biology, Therapeutic Innovation, Early Detection, Prevention and Interception.","authors":"Monte M Winslow,Mohamed A Ahmed,Christine D Berg,James R M Black,Julian Downward,Ramaswamy Govindan,Roy S Herbst,John V Heymach,Elizabeth M Jaffee,Norbert Kraut,Miriam Merad,Matthew Meyerson,Tej Pandya,Katerina Politi,Arati V Rao,Charles M Rudin,Jean Charles Soria,Yuning J Tang,Kwok-Kin Wong,Timothy A Yap,Charles Swanton","doi":"10.1158/2159-8290.cd-25-2318","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-2318","url":null,"abstract":"Advances in targeted therapies, immunotherapy, and early detection have revolutionized lung cancer treatment and extended survival. Nonetheless, lung cancer remains highly fatal. Here, we identify knowledge gaps and propose critical areas of future research, aligning with the mission of the AACR Lung Cancer Task Force. We delineate research priorities, including advancing prevention initiatives, enhancing early detection strategies, developing novel treatments, and refining patient stratification. Addressing disparities and increasing efforts on relatively neglected lung cancer subtypes are also essential. Finally, international collaboration, centralized clinical trial databases, novel clinical trial designs, and artificial intelligence-driven analytics should accelerate precision medicine and aid in elucidating drug resistance mechanisms. Together, these efforts promise to improve patient outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719477","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}
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