{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T07:47:40Z","timestamp":1778226460352,"version":"3.51.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62072145"],"award-info":[{"award-number":["62072145"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["LH2019C042"],"award-info":[{"award-number":["LH2019C042"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The link between tumor genetic variations and immunotherapy benefits has been widely recognized. Recent studies suggested that the key biological pathways activated by accumulated genetic mutations may act as an effective biomarker for predicting the efficacy of immune checkpoint inhibitor (ICI) therapy. Here, we developed a novel individual Pathway Mutation Perturbation (iPMP) method that measures the pathway mutation perturbation level by combining evidence of the cumulative effect of mutated genes with the position of mutated genes in the pathways. In iPMP, somatic mutations on a single sample were first mapped to genes in a single pathway to infer the pathway mutation perturbation score (PMPscore), and then, an integrated PMPscore profile was produced, which can be used in place of the original mutation dataset to identify associations with clinical outcomes. To illustrate the effect of iPMP, we applied it to a melanoma cohort treated with ICIs and identified seven significant perturbation pathways, which jointly constructed a pathway-based signature. With the signature, patients were classified into two subgroups with significant distinctive overall survival and objective response rate to immunotherapy. Moreover, the pathway-based signature was consistently validated in two independent melanoma cohorts. We further applied iPMP to two non-small cell lung cancer cohorts and also obtained good performance. Altogether, the iPMP method could be used to identify the significant mutation perturbation pathways for constructing the pathway-based biomarker to predict the clinical outcomes of immunotherapy. The iPMP method has been implemented as a freely available R-based package (https:\/\/CRAN.R-project.org\/package=PMAPscore).<\/jats:p>","DOI":"10.1093\/bib\/bbac360","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T21:29:05Z","timestamp":1662413345000},"source":"Crossref","is-referenced-by-count":13,"title":["A novel pathway mutation perturbation score predicts the clinical outcomes of immunotherapy"],"prefix":"10.1093","volume":"23","author":[{"given":"Xiangmei","family":"Li","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yalan","family":"He","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiashuo","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayue","family":"Qiu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Basic Medical Science, Heilongjiang University of Chinese Medicine , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3276-0819","authenticated-orcid":false,"given":"Junwei","family":"Han","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University , Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"2022092013240610000_ref1","doi-asserted-by":"crossref","first-page":"e000442","DOI":"10.1136\/esmoopen-2018-000442","article-title":"Implementing TMB measurement in clinical practice: considerations on assay requirements","volume":"4","author":"Buttner","year":"2019","journal-title":"ESMO Open"},{"key":"2022092013240610000_ref2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13073-017-0424-2","article-title":"Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden","volume":"9","author":"Chalmers","year":"2017","journal-title":"Genome Med"},{"key":"2022092013240610000_ref3","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1126\/science.aaa1348","article-title":"Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer","volume":"348","author":"Rizvi","year":"2015","journal-title":"Science"},{"key":"2022092013240610000_ref4","doi-asserted-by":"crossref","first-page":"202","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":"2022092013240610000_ref5","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1056\/NEJMoa1406498","article-title":"Genetic basis for clinical response to CTLA-4 blockade in melanoma","volume":"371","author":"Snyder","year":"2014","journal-title":"N Engl J Med"},{"key":"2022092013240610000_ref6","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/S1470-2045(17)30516-8","article-title":"Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer 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