{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:55:58Z","timestamp":1777103758675,"version":"3.51.4"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":114,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Radiotherapy is a fundamental component of rectal cancer treatment, yet patient responses remain highly heterogeneous due to the lack of reliable biomarkers supported by genomic variation evidence. Integrating multi\u2010cohort transcriptomic data with machine\u2010learning approaches enables systematic identification of genes with both predictive and therapeutic relevance. This study aimed to develop a robust model for predicting radiotherapy response and to functionally characterize CES1 as a key regulator of radiosensitivity and a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three independent GEO cohorts were standardized and integrated, followed by a comprehensive machine\u2010learning pipeline incorporating LASSO, Elastic Net, Random Forest, XGBoost, and information gain. A consensus\u2010ranked five\u2010gene model was constructed using nested cross\u2010validation. CES1, identified as the top\u2010ranked contributor to model performance, was selected for biological validation. To connect transcriptomic findings with genetic variation, copy number alteration (GISTIC2) and somatic mutation analyses were performed in TCGA\u2010READ. Functional assays\u2014including quantitative PCR, CCK\u20108 viability assays, colony formation, wound\u2010healing migration assays, Annexin V\/PI flow cytometry, and rescue by CES1 overexpression\u2014were performed in HT\u201029 and SW480 cells to evaluate its mechanistic role in radiotherapy response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The machine\u2010learning model demonstrated high discriminative accuracy across datasets and consistently highlighted CES1 as a dominant contributor to radiosensitivity prediction. CES1 expression increased after clinical chemoradiotherapy and showed dose\u2010dependent induction following irradiation in vitro. CES1 knockdown significantly reduced radiation\u2010induced apoptosis, enhanced clonogenic survival, and promoted migratory capacity, collectively indicating a radioresistant and more aggressive phenotype. Restoration of CES1 expression in CES1\u2010silenced cells reversed radioresistance and re\u2010established irradiation sensitivity. Genomic analysis in TCGA\u2010READ further demonstrated that CES1 expression was positively associated with copy number status, whereas coding\u2010sequence mutations in CES1 were infrequent, suggesting dysregulation primarily through copy\u2010number and transcriptional mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrative computational and experimental study identifies CES1 as a predictive biomarker and copy number\u2010linked regulator of radiosensitivity in rectal cancer. Modulation of CES1 directly alters cellular responses to irradiation, supporting its role as a mechanistically interpretable biomarker for response stratification. These findings align with the emerging concept that integrating genetic variation profiling with functional validation can accelerate variant\u2010to\u2010biomarker translation in precision oncology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/9790288","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:21:51Z","timestamp":1777101711000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Variant\u2010to\u2010Biomarker Integration and Mechanistic Validation Identify CES1 as a Copy Number\u2010Linked Predictor of Radiotherapy Response in Rectal Cancer"],"prefix":"10.1155","volume":"2026","author":[{"given":"Xiaodong","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingye","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxia","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7183-9485","authenticated-orcid":false,"given":"Yongxiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2020.03.011"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.101158"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(21)00079-6"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-020-04566-x"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.30097"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology13121007"},{"key":"e_1_2_11_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/17588359221077972"},{"key":"e_1_2_11_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13184642"},{"key":"e_1_2_11_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-03047-z"},{"key":"e_1_2_11_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2023.100590"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaf440"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010770"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqae079"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2018.05.005"},{"key":"e_1_2_11_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-017-0437-z"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.119.089680"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.163624"},{"key":"e_1_2_11_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10735-025-10446-y"},{"key":"e_1_2_11_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"},{"key":"e_1_2_11_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm254"},{"key":"e_1_2_11_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa980"},{"key":"e_1_2_11_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx364"},{"key":"e_1_2_11_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_11_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1716-1"},{"key":"e_1_2_11_26_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_11_27_2","doi-asserted-by":"publisher","DOI":"10.1039\/c5mb00663e"},{"key":"e_1_2_11_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_2_11_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_11_30_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i01"},{"key":"e_1_2_11_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-62"},{"key":"e_1_2_11_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neunet.2022.02.007"},{"key":"e_1_2_11_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200410135"},{"key":"e_1_2_11_34_2","doi-asserted-by":"publisher","DOI":"10.1177\/0272989x06295361"},{"key":"e_1_2_11_35_2","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2018.07.02"},{"key":"e_1_2_11_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_11_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2011.12.012"},{"key":"e_1_2_11_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.675617"},{"key":"e_1_2_11_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.862743"},{"key":"e_1_2_11_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2016.02.011"},{"key":"e_1_2_11_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11070955"},{"key":"e_1_2_11_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-018-0758-7"},{"key":"e_1_2_11_43_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.653621"},{"key":"e_1_2_11_44_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.79928"},{"key":"e_1_2_11_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0150-x"},{"key":"e_1_2_11_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.09.023"},{"key":"e_1_2_11_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-024-04995-1"},{"key":"e_1_2_11_48_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1184794"},{"key":"e_1_2_11_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01383-x"},{"key":"e_1_2_11_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.597673"},{"key":"e_1_2_11_51_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-21-1059"}],"container-title":["Human Mutation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/9790288","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/humu\/9790288","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/9790288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T07:21:52Z","timestamp":1777101712000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/humu\/9790288"}},"subtitle":[],"editor":[{"given":"Hao","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/humu\/9790288"],"URL":"https:\/\/doi.org\/10.1155\/humu\/9790288","archive":["Portico"],"relation":{},"ISSN":["1059-7794","1098-1004"],"issn-type":[{"value":"1059-7794","type":"print"},{"value":"1098-1004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-12-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"9790288"}}