{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T01:08:33Z","timestamp":1774487313811,"version":"3.50.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170675"],"award-info":[{"award-number":["32170675"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Heilongjiang Postdoctoral Scientific Research Developmental Fund","award":["LBH-Q20147"],"award-info":[{"award-number":["LBH-Q20147"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cancer development and progression are driven by the accumulation of somatic genetic alterations, which occur in a specific temporal order. However, how the order of mutations impacts cancer phenotypes of solid tumors remains poorly understood. To address this, we developed a novel computational framework, IMOP-Cancer (Identifying Mutation Order Pairs in Cancer), to identify mutation gene pairs whose order influences cancer phenotypes. We applied IMOP-Cancer to The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) cohort and identified 446 key mutation order pairs, with 34 pairs significantly associated with prognosis. Mutation order impacts cancer phenotypes, as demonstrated by CSMD3 and PTPRD (tumor proliferation) and TP53 and NAV3 (immune modulation), with effects validated in four independent datasets. We further presented the impact of mutation pairs on cancer phenotypes through case studies in the TCGA cohorts of bladder urothelial carcinoma (BLCA), and colon adenocarcinoma (COAD). We extended this analysis to 33 cancer cohorts from TCGA portal, identifying 106\u00a0034 critical mutation pairs across 17 cancers, with 3036 pairs co-occurring in multiple cancers. Shared mutation pairs across cancers also showed distinct effects on cancer phenotype. Our study highlights the importance of mutation order in cancer progression and diversity, offering new insights into the temporal dynamics of co-occurring mutations and paving the way for personalized treatment strategies and improved diagnosis.<\/jats:p>","DOI":"10.1093\/bib\/bbaf362","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T07:47:47Z","timestamp":1751701667000},"source":"Crossref","is-referenced-by-count":1,"title":["IMOP-Cancer: identifying mutation order pairs impacting cancer phenotypes"],"prefix":"10.1093","volume":"26","author":[{"given":"Yijing","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Shaobo","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Renjie","family":"Dou","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Wanmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Yuanyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Dongxue","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"given":"Fangfang","family":"Fan","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1810-1200","authenticated-orcid":false,"given":"Yanyan","family":"Ping","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road , Nangang District, Harbin , Heilongjiang Province, 150081,","place":["China"]}]}],"member":"286","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"2025072307064662000_ref1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1126\/science.959840","article-title":"The clonal evolution of tumor cell populations","volume":"194","author":"Nowell","year":"1976","journal-title":"Science"},{"key":"2025072307064662000_ref2","first-page":"3643","article-title":"The genetic origin of drug resistance in neoplasms: Implications for systemic therapy","volume":"44","author":"Goldie","year":"1984","journal-title":"Cancer Res"},{"key":"2025072307064662000_ref3","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1016\/j.cell.2012.04.023","article-title":"The life history of 21 breast cancers","volume":"149","author":"Nik-Zainal","year":"2012","journal-title":"Cell"},{"key":"2025072307064662000_ref4","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/ng.3175","article-title":"Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression","volume":"47","author":"Takeda","year":"2015","journal-title":"Nat Genet"},{"key":"2025072307064662000_ref5","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","article-title":"Tracking the evolution of non-small-cell lung cancer","volume":"376","author":"Jamal-Hanjani","year":"2017","journal-title":"N Engl J Med"},{"key":"2025072307064662000_ref6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.cell.2018.02.020","article-title":"Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal","volume":"173","author":"Mitchell","year":"2018","journal-title":"Cell"},{"key":"2025072307064662000_ref7","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41586-019-1907-7","article-title":"The evolutionary history of 2,658 cancers","volume":"578","author":"Gerstung","year":"2020","journal-title":"Nature"},{"key":"2025072307064662000_ref8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020415","article-title":"Comprehensive analysis of Co-mutations identifies cooperating mechanisms of tumorigenesis","volume":"14","author":"Jiang","year":"2022","journal-title":"Cancer"},{"key":"2025072307064662000_ref9","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac725","article-title":"CoMutDB: The landscape of somatic mutation co-occurrence in cancers","volume":"39","author":"Jiang","year":"2023","journal-title":"Bioinformatics"},{"key":"2025072307064662000_ref10","article-title":"Unbiased co-occurring mutational landscapes in tumorigenesis","author":"Li","year":"2025","journal-title":"BioRxiv"},{"key":"2025072307064662000_ref11","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s13073-024-01376-7","article-title":"Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios","volume":"16","author":"Han","year":"2024","journal-title":"Genome Med"},{"key":"2025072307064662000_ref12","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.jhep.2022.11.030","article-title":"Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma","volume":"78","author":"Kendre","year":"2023","journal-title":"J Hepatol"},{"key":"2025072307064662000_ref13","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s12943-024-02173-x","article-title":"Co-occurring mutations identify prognostic subgroups of microsatellite stable colorectal cancer","volume":"23","author":"Nunes","year":"2024","journal-title":"Mol Cancer"},{"key":"2025072307064662000_ref14","doi-asserted-by":"publisher","first-page":"1002700","DOI":"10.1371\/journal.pgen.1002700","article-title":"Acquisition order of Ras and p53 gene alterations defines distinct adrenocortical tumor phenotypes","volume":"8","author":"Grimes","year":"2012","journal-title":"PLoS Genet"},{"key":"2025072307064662000_ref15","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1056\/NEJMoa1412098","article-title":"Effect of mutation order on myeloproliferative neoplasms","volume":"372","author":"Ortmann","year":"2015","journal-title":"N Engl J Med"},{"key":"2025072307064662000_ref16","doi-asserted-by":"publisher","first-page":"e438","DOI":"10.3324\/haematol.2015.129510","article-title":"Peter J Campbell 1, Anthony R Green, DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype","volume":"100","author":"Jyoti Nangalia","year":"2015","journal-title":"Haematologica"},{"key":"2025072307064662000_ref17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33189-w","article-title":"HOXA9 has the hallmarks of a biological switch with implications in blood cancers. Nature","volume":"13","author":"Talarmain","year":"2022","journal-title":"Communications"},{"key":"2025072307064662000_ref18","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ccell.2018.11.009","article-title":"The roles of initiating truncal mutations in human cancers: The order of mutations and tumor cell type matters","volume":"35","author":"Levine","year":"2019","journal-title":"Cancer Cell"},{"key":"2025072307064662000_ref19","doi-asserted-by":"publisher","first-page":"a027060","DOI":"10.1101\/cshperspect.a027060","article-title":"Order matters: The order of somatic mutations influences cancer evolution","volume":"7","author":"Kent","year":"2017","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2025072307064662000_ref20","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1016\/j.ccell.2024.10.009","article-title":"In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy","volume":"42","author":"Bowman","year":"2024","journal-title":"Cancer Cell"},{"key":"2025072307064662000_ref21","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1038\/s41375-024-02211-z","article-title":"Mutation order in acute myeloid leukemia identifies uncommon patterns of evolution and illuminates phenotypic heterogeneity","volume":"38","author":"Schwede","year":"2024","journal-title":"Leukemia"},{"key":"2025072307064662000_ref22","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The cancer genome atlas pan-cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat Genet"},{"key":"2025072307064662000_ref23","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","author":"Lonsdale","year":"2013","journal-title":"Nat Genet"},{"key":"2025072307064662000_ref24","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/s41588-023-01355-5","article-title":"Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer","volume":"55","author":"Ravi","year":"2023","journal-title":"Nat Genet"},{"key":"2025072307064662000_ref25","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci Signal"},{"key":"2025072307064662000_ref26","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a cancer dependency map","volume":"170","author":"Tsherniak","year":"2017","journal-title":"Cell"},{"key":"2025072307064662000_ref27","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"2025072307064662000_ref28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2025072307064662000_ref29","doi-asserted-by":"publisher","first-page":"a026625","DOI":"10.1101\/cshperspect.a026625","article-title":"Principles of reconstructing the subclonal architecture of cancers","volume":"7","author":"Dentro","year":"2017","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2025072307064662000_ref30","article-title":"Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment","author":"Leshchiner","year":"2019","journal-title":"BioRxiv"},{"key":"2025072307064662000_ref31","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature08460","article-title":"Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1","volume":"462","author":"Barbie","year":"2009","journal-title":"Nature"},{"key":"2025072307064662000_ref32","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1056\/NEJMoa1507643","article-title":"Nivolumab versus docetaxel in advanced nonsquamous non\u2013small-cell lung cancer","volume":"373","author":"Borghaei","year":"2015","journal-title":"N Engl J Med"},{"key":"2025072307064662000_ref33","doi-asserted-by":"publisher","first-page":"100966","DOI":"10.1016\/j.neo.2024.100966","article-title":"Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma","volume":"48","author":"Wang","year":"2024","journal-title":"Neoplasia"},{"key":"2025072307064662000_ref34","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1126\/science.1133427","article-title":"The consensus coding sequences of human breast and colorectal cancers","volume":"314","author":"Sj\u00f6blom","year":"2006","journal-title":"Science"},{"key":"2025072307064662000_ref35","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.molcel.2018.06.012","article-title":"A systematic p53 mutation library links differential functional impact to cancer mutation pattern and evolutionary conservation","volume":"71","author":"Kotler","year":"2018","journal-title":"Mol Cell"},{"key":"2025072307064662000_ref36","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nature13385","article-title":"Comprehensive molecular profiling of lung adenocarcinoma","volume":"511","author":"Cancer Genome Atlas Research Network","year":"2014","journal-title":"Nature"},{"key":"2025072307064662000_ref37","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1182\/blood.2022017578","article-title":"Genetic basis and molecular profiling in myeloproliferative neoplasms","volume":"141","author":"Luque Paz","year":"2023","journal-title":"Blood"},{"key":"2025072307064662000_ref38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27472-5","article-title":"Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia","volume":"12","author":"Benard","year":"2021","journal-title":"Nat Commun"},{"key":"2025072307064662000_ref39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13001-y","article-title":"Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes","volume":"10","author":"Nagata","year":"2019","journal-title":"Nat Commun"},{"key":"2025072307064662000_ref40","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1038\/s41591-018-0115-6","article-title":"Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib","volume":"24","author":"Quek","year":"2018","journal-title":"Nat Med"},{"key":"2025072307064662000_ref41","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1038\/nrclinonc.2013.42","article-title":"The future of epigenetic therapy in solid tumours\u2014Lessons from the past","volume":"10","author":"Azad","year":"2013","journal-title":"Nat Rev Clin Oncol"},{"key":"2025072307064662000_ref42","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16030514","article-title":"Molecular genetic profile of Myelofibrosis: Implications in the diagnosis, prognosis, and treatment advancements","volume":"16","author":"Verma","year":"2024","journal-title":"Cancer"},{"key":"2025072307064662000_ref43","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.hoc.2021.01.001","article-title":"Epigenetic dysregulation of myeloproliferative neoplasms","volume":"35","author":"Dunbar","year":"2021","journal-title":"Hematol Oncol Clin North Am"},{"key":"2025072307064662000_ref44","doi-asserted-by":"publisher","first-page":"eabg5601","DOI":"10.1126\/science.abg5601","article-title":"Genome-wide analysis of somatic noncoding mutation patterns in cancer","volume":"376","author":"Dietlein","year":"2022","journal-title":"Science"},{"key":"2025072307064662000_ref45","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1158\/0008-5472.CAN-22-3558","article-title":"Breast cancer mutations HER2V777L and PIK3CAH1047R activate the p21\u2013CDK4\/6\u2013cyclin D1 Axis to drive tumorigenesis and drug resistance","volume":"83","author":"Cheng","year":"2023","journal-title":"Cancer Res"},{"key":"2025072307064662000_ref46","doi-asserted-by":"publisher","first-page":"e268","DOI":"10.1016\/S1470-2045(13)70591-6","article-title":"Classification of endometrial carcinoma: More than two types","volume":"15","author":"Murali","year":"2014","journal-title":"Lancet Oncol"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/4\/bbaf362\/63828767\/bbaf362.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/4\/bbaf362\/63828767\/bbaf362.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T11:06:51Z","timestamp":1753268811000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf362\/8210811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf362","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,7]]},"published":{"date-parts":[[2025,7]]},"article-number":"bbaf362"}}