Pub Date : 2025-12-02DOI: 10.1158/2159-8290.CD-24-1590
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
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 with 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 cells while expanding Tet2-mutant CH clones in mice. The 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.
Significance: This study identifies elevated CH with distinct, nonclassical mutations in 9/11 first responders, particularly younger individuals, and links CH to increased leukemia risk. Findings suggest broader relevance to other genotoxic environmental exposures and highlight IL1RAP as a critical driver of CH expansion and a promising therapeutic target for inflammation-driven malignancies. See related commentary by Safina and van Galen, p. 2406.
环境暴露与癌前血液病有关，但明确暴露的队列研究有限。我们对9/11世界贸易中心（WTC）灾难中暴露于雾化粉尘和致癌物的大量第一反应者的血液样本进行了测序，并在控制了年龄、种族和性别后，与两组对照队列相比，观察到克隆造血（CH）突变的发生率明显更高。年轻暴露的第一反应者表现出非常规的CH突变，具有缺陷的DNA修复特征。与不含CH的WTC暴露应答者相比，有CH的WTC暴露应答者白血病风险升高（3.7% vs. 0.6%， OR=5.73）。暴露于从WTC部位收集的颗粒物会损害健康干细胞，同时扩大小鼠的tet2突变CH克隆。炎症传感器IL1RAP在小鼠CH中过表达，基因敲低可抑制突变克隆的体内生长。这项研究将离散的环境暴露与造血突变和白血病联系起来，确定IL1RAP是CH的一个新的治疗靶点。
{"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":"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 with 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 cells while expanding Tet2-mutant CH clones in mice. The 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><p><strong>Significance: </strong>This study identifies elevated CH with distinct, nonclassical mutations in 9/11 first responders, particularly younger individuals, and links CH to increased leukemia risk. Findings suggest broader relevance to other genotoxic environmental exposures and highlight IL1RAP as a critical driver of CH expansion and a promising therapeutic target for inflammation-driven malignancies. See related commentary by Safina and van Galen, p. 2406.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2468-2484"},"PeriodicalIF":33.3,"publicationDate":"2025-12-02","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}
Pub Date : 2025-12-02DOI: 10.1158/2159-8290.CD-25-1833
Elsa Bernard, Isidro Cortés-Ciriano, Federico Gaiti, Siting Gan, Sizun Jiang, Marta Kovatcheva, Marlies Meisel, Nathan E Reticker-Flynn, Alison M Schram, Ofer Shoshani, Dana Silverbush, Varun Venkataramani, Clare E Weeden, Xin Zhou
{"title":"Reflections on Advances in Cancer Research in 2025.","authors":"Elsa Bernard, Isidro Cortés-Ciriano, Federico Gaiti, Siting Gan, Sizun Jiang, Marta Kovatcheva, Marlies Meisel, Nathan E Reticker-Flynn, Alison M Schram, Ofer Shoshani, Dana Silverbush, Varun Venkataramani, Clare E Weeden, Xin Zhou","doi":"10.1158/2159-8290.CD-25-1833","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-25-1833","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 12","pages":"2422-2430"},"PeriodicalIF":33.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653645","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}
Pub Date : 2025-12-02DOI: 10.1158/2159-8290.CD-25-1782
Lillian L Siu
Adapted excerpts from the 15th edition of the annual American Association for Cancer Research Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to the US Congress and the public highlight significant strides made possible through medical research, much of which is supported by federal investments in the NIH, NCI, FDA, and Centers for Disease Control and Prevention.
{"title":"Cancer in 2025.","authors":"Lillian L Siu","doi":"10.1158/2159-8290.CD-25-1782","DOIUrl":"10.1158/2159-8290.CD-25-1782","url":null,"abstract":"<p><p>Adapted excerpts from the 15th edition of the annual American Association for Cancer Research Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to the US Congress and the public highlight significant strides made possible through medical research, much of which is supported by federal investments in the NIH, NCI, FDA, and Centers for Disease Control and Prevention.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 12","pages":"2408-2413"},"PeriodicalIF":33.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653655","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}
Pub Date : 2025-12-02DOI: 10.1158/2159-8290.cd-25-1584
Ksenia R. Safina, Peter van Galen
Summary: In this issue, Verma, Zeig-Owens, Goldfarb, and colleagues report that increased prevalence of clonal hematopoiesis (CH) among 9/11 World Trade Center first responders is accompanied by uncharacteristic mutations in younger responders and an elevated risk of blood cancer. Using a mouse model of CH, they connect the clonal expansion triggered by World Trade Center particulate matter exposure to higher levels of IL1RAP, offering a new potential target to limit clonal expansion and reduce CH-associated risks. See related article by Verma et al., p. 2468
{"title":"Lingering Effects: Environmental Exposure Leads to Clonal Hematopoiesis via IL1RAP in 9/11 First Responders","authors":"Ksenia R. Safina, Peter van Galen","doi":"10.1158/2159-8290.cd-25-1584","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1584","url":null,"abstract":"Summary: In this issue, Verma, Zeig-Owens, Goldfarb, and colleagues report that increased prevalence of clonal hematopoiesis (CH) among 9/11 World Trade Center first responders is accompanied by uncharacteristic mutations in younger responders and an elevated risk of blood cancer. Using a mouse model of CH, they connect the clonal expansion triggered by World Trade Center particulate matter exposure to higher levels of IL1RAP, offering a new potential target to limit clonal expansion and reduce CH-associated risks. See related article by Verma et al., p. 2468","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"18 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651225","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}
Pub Date : 2025-12-02DOI: 10.1158/2159-8290.CD-25-1639
Pei-Ling Chen, Whijae Roh, Alexandre Reuben, Zachary A Cooper, Christine N Spencer, Peter A Prieto, John P Miller, Roland L Bassett, Vancheswaran Gopalakrishnan, Khalida Wani, Mariana Petaccia De Macedo, Jacob L Austin-Breneman, Hong Jiang, Qing Chang, Sangeetha M Reddy, Wei-Shen Chen, Michael T Tetzlaff, Russell J Broaddus, Michael A Davies, Jeffrey E Gershenwald, Lauren Haydu, Alexander J Lazar, Sapna P Patel, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Isabella C Glitza, Scott E Woodman, Luis M Vence, Ignacio I Wistuba, Rodabe N Amaria, Lawrence N Kwong, Victor Prieto, R Eric Davis, Wencai Ma, Willem W Overwijk, Arlene H Sharpe, Jianhua Hu, P Andrew Futreal, Jorge Blando, Padmanee Sharma, James P Allison, Lynda Chin, Jennifer A Wargo
{"title":"Editor's Note: Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.","authors":"Pei-Ling Chen, Whijae Roh, Alexandre Reuben, Zachary A Cooper, Christine N Spencer, Peter A Prieto, John P Miller, Roland L Bassett, Vancheswaran Gopalakrishnan, Khalida Wani, Mariana Petaccia De Macedo, Jacob L Austin-Breneman, Hong Jiang, Qing Chang, Sangeetha M Reddy, Wei-Shen Chen, Michael T Tetzlaff, Russell J Broaddus, Michael A Davies, Jeffrey E Gershenwald, Lauren Haydu, Alexander J Lazar, Sapna P Patel, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Isabella C Glitza, Scott E Woodman, Luis M Vence, Ignacio I Wistuba, Rodabe N Amaria, Lawrence N Kwong, Victor Prieto, R Eric Davis, Wencai Ma, Willem W Overwijk, Arlene H Sharpe, Jianhua Hu, P Andrew Futreal, Jorge Blando, Padmanee Sharma, James P Allison, Lynda Chin, Jennifer A Wargo","doi":"10.1158/2159-8290.CD-25-1639","DOIUrl":"10.1158/2159-8290.CD-25-1639","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 12","pages":"2574"},"PeriodicalIF":33.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653634","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}
Pub Date : 2025-11-27DOI: 10.1158/2159-8290.cd-nw2025-0105
Siddhartha Mukherjee, MD, DPhil, has written four new chapters for an updated version of his acclaimed book on the history of cancer, The Emperor of All Maladies. Released today, the book discusses new developments in cancer prevention, detection, and treatment. Here, he shares his motive for updating the book, as well as his thoughts on future directions for cancer research.
医学博士悉达多·慕克吉（Siddhartha Mukherjee）为他广受好评的关于癌症历史的书《万病之王》（the Emperor of All diseases）的更新版本写了四个新的章节。今天出版的这本书讨论了癌症预防、检测和治疗方面的新进展。在这里，他分享了他更新这本书的动机，以及他对癌症研究未来方向的看法。
{"title":"Q&A: Siddhartha Mukherjee on New Edition of The Emperor of All Maladies.","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0105","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0105","url":null,"abstract":"Siddhartha Mukherjee, MD, DPhil, has written four new chapters for an updated version of his acclaimed book on the history of cancer, The Emperor of All Maladies. Released today, the book discusses new developments in cancer prevention, detection, and treatment. Here, he shares his motive for updating the book, as well as his thoughts on future directions for cancer research.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644901","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}
Standard of care for advanced cervical cancer includes chemotherapy, anti-angiogenic and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. De-escalation chemotherapy together with immunotargeted therapies have been proven effective and less toxic in other cancers. Here, we conducted a multicenter, single-arm, phase 2 study of first-line de-escalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in PD-L1 positive, persistent, recurrent or metastatic cervical cancer patients. Of 32 efficacy evaluable patients, 30 (93.8%, 95% CI: 79.2% to 99.2%) had an investigators-confirmed objective response. Single nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells and activated germinal-center B cells portended optimal treatment response. Patients with a high TLS-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in metastatic, persistent, or recurrent cervical cancer patients.
{"title":"Molecular and immune correlates of response to first-line de-escalated chemotherapy plus penpulimab and anlotinib in advanced cervical cancer","authors":"Qin Xu, Zhengrong Deng, Jing Liu, Yanhong Zhuo, Fei Zhu, Lele Chang, Qin Liu, Yajuan Fu, Peiwei Li, Yunyun Liu, Songhua Huang, Li Li, Xingyun Xie, Ying Chen, Yingtao Lin, Lele Zang, Meifang Ke, Li Chen, Xiaoxia Huang, Cong Wang, Yanhong Wang, Yaxin Kang, Yuqin Wang, Mingxuan Zhu, Huiqi Zhang, Zhixin Wang, Peidong Zhang, Dan Hu, Huaiwu Lu, Yang Sun, Shengtao Zhou","doi":"10.1158/2159-8290.cd-25-1315","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1315","url":null,"abstract":"Standard of care for advanced cervical cancer includes chemotherapy, anti-angiogenic and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. De-escalation chemotherapy together with immunotargeted therapies have been proven effective and less toxic in other cancers. Here, we conducted a multicenter, single-arm, phase 2 study of first-line de-escalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in PD-L1 positive, persistent, recurrent or metastatic cervical cancer patients. Of 32 efficacy evaluable patients, 30 (93.8%, 95% CI: 79.2% to 99.2%) had an investigators-confirmed objective response. Single nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells and activated germinal-center B cells portended optimal treatment response. Patients with a high TLS-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in metastatic, persistent, or recurrent cervical cancer patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"194 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609802","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}
Pub Date : 2025-11-25DOI: 10.1158/2159-8290.cd-nw2025-0104
Two recent studies analyzing cancer genome data suggest that microbial DNA is not a common feature across most tumors, challenging earlier suggestions of a pan-cancer microbiome. Colorectal cancer stands as an exception, with one study providing strong evidence of a microbial signature. Oral cancer may also be an exception. Both studies point to contamination as a key driver of false signals.
{"title":"Studies Challenge Cancer–Microbiome Links","authors":"","doi":"10.1158/2159-8290.cd-nw2025-0104","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2025-0104","url":null,"abstract":"Two recent studies analyzing cancer genome data suggest that microbial DNA is not a common feature across most tumors, challenging earlier suggestions of a pan-cancer microbiome. Colorectal cancer stands as an exception, with one study providing strong evidence of a microbial signature. Oral cancer may also be an exception. Both studies point to contamination as a key driver of false signals.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"148 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599571","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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