{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:44:14Z","timestamp":1792619054642,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the\n                      <jats:italic>TP53<\/jats:italic>\n                      \/\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      \/\n                      <jats:italic>ATM<\/jats:italic>\n                      mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad\/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among all 881 patients with bladder cancer, the mutation frequency of\n                      <jats:italic>TP53<\/jats:italic>\n                      ,\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      , and\n                      <jats:italic>ATM<\/jats:italic>\n                      ranked in the top 20 mutated genes. The\n                      <jats:italic>TP53<\/jats:italic>\n                      \/\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      \/\n                      <jats:italic>ATM<\/jats:italic>\n                      mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P&amp;lt;0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad\/Dana-Farber cohort. Lower expression of PD-1\/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study constructed a\n                      <jats:italic>TP53<\/jats:italic>\n                      \/\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      \/\n                      <jats:italic>ATM<\/jats:italic>\n                      mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2021.643282","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:35:18Z","timestamp":1628037318000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Predictive Value of the TP53\/PIK3CA\/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy"],"prefix":"10.3389","volume":"12","author":[{"given":"Yi-Hui","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Xing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Zheng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s40425-017-0299-1","article-title":"Biomarkers for Immunotherapy in Bladder Cancer: A Moving Target","volume":"5","author":"Aggen","year":"2017","journal-title":"J Immunother Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0140-6736(16)32455-2","article-title":"Atezolizumab as First-Line Treatment in Cisplatin-Ineligible Patients With Locally Advanced and Metastatic Urothelial Carcinoma: A Single-Arm, Multicentre, Phase 2 Trial","volume":"389","author":"Balar","year":"2017","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00561-4","article-title":"Atezolizumab in Patients With Locally Advanced and Metastatic Urothelial Carcinoma Who Have Progressed Following Treatment With Platinum-Based Chemotherapy: A Single-Arm, Multicentre, Phase 2 Trial","volume":"387","author":"Rosenberg","year":"2016","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30065-7","article-title":"Nivolumab in Metastatic Urothelial Carcinoma After Platinum Therapy (CheckMate 275): A Multicentre, Single-Arm, Phase 2 Trial","volume":"18","author":"Sharma","year":"2017","journal-title":"Lancet Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1613683","article-title":"Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma","volume":"376","author":"Bellmunt","year":"2017","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0312-8","article-title":"Tumor Mutational Load Predicts Survival After Immunotherapy Across Multiple Cancer Types","volume":"51","author":"Samstein","year":"2019","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau0447","article-title":"Genetic Diversity of Tumors With Mismatch Repair Deficiency Influences Anti-PD-1 Immunotherapy Response","volume":"364","author":"Mandal","year":"2019","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.1046","article-title":"Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers: A Systematic Review and Meta-Analysis","volume":"6","author":"Petrelli","year":"2020","journal-title":"JAMA Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1911895","DOI":"10.1001\/jamanetworkopen.2019.11895","article-title":"Association of Tumor Protein P53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non-Small Cell Lung Cancer","volume":"2","author":"Chen","year":"2019","journal-title":"JAMA Netw Open"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2963","article-title":"Evaluation of POLE and POLD1 Mutations as Biomarkers for Immunotherapy Outcomes Across Multiple Cancer Types","volume":"50","author":"Wang","year":"2019","journal-title":"JAMA Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.7740","article-title":"Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1\/PD-L1 Blockade in Advanced Urothelial Cancers","volume":"36","author":"Teo","year":"2018","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s40425-019-0619-8","article-title":"DNA Damage Repair Gene Mutations and Their Association With Tumor Immune Regulatory Gene Expression in Muscle Invasive Bladder Cancer Subtypes","volume":"7","author":"Vidotto","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"eabc4220","DOI":"10.1126\/scitranslmed.abc4220","article-title":"ARID1A Mutation Plus CXCL13 Expression Act as Combinatorial Biomarkers to Predict Responses to Immune Checkpoint Therapy in mUCC","volume":"12","author":"Goswami","year":"2020","journal-title":"Sci Transl Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4333","article-title":"Mutational Landscape of Metastatic Cancer Revealed From Prospective Clinical Sequencing of 10,000 Patients","volume":"23","author":"Zehir","year":"2017","journal-title":"Nat Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.cell.2017.09.007","article-title":"Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer","volume":"171","author":"Robertson","year":"2017","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3692","article-title":"Clonal Evolution of Chemotherapy-Resistant Urothelial Carcinoma","volume":"48","author":"Faltas","year":"2016","journal-title":"Nat Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0623","article-title":"Somatic ERCC2 Mutations Correlate With Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma","volume":"4","author":"Van Allen","year":"2014","journal-title":"Cancer Discovery"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0200-2","article-title":"Genomic Correlates of Response to Immune Checkpoint Blockade in Microsatellite-Stable Solid Tumors","volume":"50","author":"Miao","year":"2018","journal-title":"Nat Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The Cbio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nature25501","article-title":"TGFbeta Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0713","article-title":"X-Tile: A New Bio-Informatics Tool for Biomarker Assessment and Outcome-Based Cut-Point Optimization","volume":"10","author":"Camp","year":"2004","journal-title":"Clin Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: Efficient and Comprehensive Analysis of Somatic Variants in Cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring Tumour Purity and Stromal and Immune Cell Admixture From Expression Data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust Enumeration of Cell Subsets From Tissue Expression Profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B26","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive Analyses of Tumor Immunity: Implications for Cancer Immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477","article-title":"Signatures of Mutational Processes in Human Cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21631","article-title":"Treatment of Muscle-Invasive and Advanced Bladder Cancer in 2020","volume":"70","author":"Patel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500596","article-title":"PD-1 Blockade in Tumors With Mismatch-Repair Deficiency","volume":"372","author":"Le","year":"2015","journal-title":"N Engl J Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.annonc.2020.01.065","article-title":"Clinical and Molecular Correlates of PD-L1 Expression in Patients With Lung Adenocarcinomas","volume":"31","author":"Schoenfeld","year":"2020","journal-title":"Ann Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc3421","article-title":"Microbiome-Derived Inosine Modulates Response to Checkpoint Inhibitor Immunotherapy","volume":"369","author":"Mager","year":"2020","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1490","article-title":"Clonal Neoantigens Elicit T Cell Immunoreactivity and Sensitivity to Immune Checkpoint Blockade","volume":"351","author":"McGranahan","year":"2016","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.1061","article-title":"Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review","volume":"2","author":"Stanton","year":"2016","journal-title":"JAMA Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2015.2151","article-title":"Association of Polymerase E-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1","volume":"1","author":"Howitt","year":"2015","journal-title":"JAMA Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2858","article-title":"Genomic Instability\u2013an Evolving Hallmark of Cancer","volume":"11","author":"Negrini","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.049","article-title":"Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification Within and Across Tissues of Origin","volume":"158","author":"Hoadley","year":"2014","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw437","article-title":"Mutation Profiles in Early-Stage Lung Squamous Cell Carcinoma With Clinical Follow-Up and Correlation With Markers of Immune Function","volume":"28","author":"Choi","year":"2017","journal-title":"Ann Oncol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13045-019-0762-1","article-title":"Genomic Landscape and its Correlations With Tumor Mutational Burden, PD-L1 Expression, and Immune Cells Infiltration in Chinese Lung Squamous Cell Carcinoma","volume":"12","author":"Jiang","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.immuni.2020.06.016","article-title":"An Oncogenic Alteration Creates a Microenvironment That Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells","volume":"53","author":"Kumagai","year":"2020","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e1581556","DOI":"10.1080\/2162402X.2019.1581556","article-title":"Inhibition of PI3K Pathway Increases Immune Infiltrate in Muscle-Invasive Bladder Cancer","volume":"8","author":"Borcoman","year":"2019","journal-title":"Oncoimmunology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nrm3546","article-title":"The ATM Protein Kinase: Regulating the Cellular Response to Genotoxic Stress, and More","volume":"14","author":"Shiloh","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3347","DOI":"10.1038\/ncomms4347","article-title":"ATM Specifically Mediates Repair of Double-Strand Breaks With Blocked DNA Ends","volume":"5","author":"Alvarez-Quilon","year":"2014","journal-title":"Nat Commun"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1815309","article-title":"The Combined Status of ATM and P53 Link Tumor Development With Therapeutic Response","volume":"23","author":"Jiang","year":"2009","journal-title":"Genes Dev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2008.06.018","article-title":"Comparison of Nonhomologous End Joining and Homologous Recombination in Human Cells","volume":"7","author":"Mao","year":"2008","journal-title":"DNA Repair (Amst)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.04.007","article-title":"Glycolytic Activation of Peritumoral Monocytes Fosters Immune Privilege via the PFKFB3-PD-L1 Axis in Human Hepatocellular Carcinoma","volume":"71","author":"Chen","year":"2019","journal-title":"J Hepatol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2106","article-title":"Programmed Death-1-Induced Interleukin-10 Production by Monocytes Impairs CD4+ T Cell Activation During HIV Infection","volume":"16","author":"Said","year":"2010","journal-title":"Nat Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0793","article-title":"Long-Term Survival in Patients Responding to Anti-PD-1\/PD-L1 Therapy and Disease Outcome Upon Treatment Discontinuation","volume":"25","author":"Gauci","year":"2019","journal-title":"Clin Cancer Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.643282\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:35:22Z","timestamp":1628037322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.643282\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,4]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.643282"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.643282","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,4]]},"article-number":"643282"}}