{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T02:29:51Z","timestamp":1782095391594,"version":"3.54.5"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T00:00:00Z","timestamp":1657324800000},"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\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["T32 CA094186"],"award-info":[{"award-number":["T32 CA094186"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["K25 DK115904"],"award-info":[{"award-number":["K25 DK115904"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["P30 CA043703"],"award-info":[{"award-number":["P30 CA043703"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["P20 CA233216"],"award-info":[{"award-number":["P20 CA233216"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["U54 CA163060"],"award-info":[{"award-number":["U54 CA163060"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["P50 CA150964"],"award-info":[{"award-number":["P50 CA150964"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["R21 CA248138"],"award-info":[{"award-number":["R21 CA248138"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["R01 CA217992"],"award-info":[{"award-number":["R01 CA217992"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009275","name":"DeGregorio Family Foundation","doi-asserted-by":"publisher","award":["R01 LM013067"],"award-info":[{"award-number":["R01 LM013067"]}],"id":[{"id":"10.13039\/100009275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently mutated driver genes but therapeutic targeting of these oncogenes remains challenging. However, the vast number of genes mutated infrequently across cancers has received less attention, in part, due to a lack of understanding of their biological significance. We present SYSMut, an extendable systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multiomics profiles in primary tumors. We establish SYSMut\u2019s improved performance vis-\u00e0-vis state-of-the-art driver gene identification methodologies by recapitulating the functional impact of known driver genes, while additionally identifying novel functionally impactful mutated genes across 29 cancers. Subsequent application of SYSMut on low-frequency gene mutations in head and neck squamous cell (HNSC) cancers, followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC cancers. SYSMut is thus a robust scalable framework that enables the discovery of new targetable avenues in cancer.<\/jats:p>","DOI":"10.1093\/bib\/bbac280","type":"journal-article","created":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T03:17:03Z","timestamp":1657336623000},"source":"Crossref","is-referenced-by-count":2,"title":["SYSMut: decoding the functional significance of rare somatic mutations in cancer"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-1446","authenticated-orcid":false,"given":"Sirvan","family":"Khalighi","sequence":"first","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"},{"name":"Department of Genetics and genome Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peronne","family":"Joseph","sequence":"additional","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Babu","sequence":"additional","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salendra","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"LaFramboise","sequence":"additional","affiliation":[{"name":"Department of Genetics and genome Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishore","family":"Guda","sequence":"additional","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"},{"name":"Digestive Health Research Institute"},{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH-44106 U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay","family":"Varadan","sequence":"additional","affiliation":[{"name":"Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,9]]},"reference":[{"key":"2022071906210992000_ref1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nature07943","article-title":"The cancer genome","volume":"458","author":"Stratton","year":"2009","journal-title":"Nature"},{"key":"2022071906210992000_ref2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer and the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"2022071906210992000_ref3","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.cell.2020.01.032","article-title":"Passenger mutations in more than 2,500 cancer genomes: overall molecular functional impact and consequences","volume":"180","author":"Kumar","year":"2020","journal-title":"Cell"},{"key":"2022071906210992000_ref4","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRAS G12C inhibition with Sotorasib in advanced solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N Engl J Med"},{"key":"2022071906210992000_ref5","article-title":"HER2-targeted therapies\u2014a role beyond breast cancer","volume-title":"Nat Rev Clin Oncol","author":"Oh","year":"2019"},{"key":"2022071906210992000_ref6","first-page":"2382","article-title":"Acquired resistance to KRASG12C inhibition in cancer","volume":"384","author":"Awad","year":"2021","journal-title":"Mass Med Soc"},{"key":"2022071906210992000_ref7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41416-019-0635-y","article-title":"Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer","volume":"122","author":"Hunter","year":"2019","journal-title":"Br J Cancer"},{"key":"2022071906210992000_ref8","first-page":"1","article-title":"Diverse alterations associated with resistance to KRAS(G12C) inhibition","volume":"2021","author":"Zhao","year":"2021","journal-title":"Nat"},{"key":"2022071906210992000_ref9","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.jgg.2020.11.001","article-title":"Untangling a complex web: computational analyses of tumor molecular profiles to decode driver mechanisms","volume":"47","author":"Khalighi","year":"2020","journal-title":"J Genet Genom"},{"key":"2022071906210992000_ref10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1126\/science.1133427","article-title":"The consensus coding sequences of human breast and colorectal cancers","volume":"314","author":"Sjoblom","year":"2006","journal-title":"Science (80-)"},{"key":"2022071906210992000_ref11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gm524","article-title":"Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine","volume":"6","author":"Raphael","year":"2014","journal-title":"Genome Med"},{"key":"2022071906210992000_ref12","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1101\/gr.134635.111","article-title":"MuSiC: identifying mutational significance in cancer genomes","volume":"22","author":"Dees","year":"2012","journal-title":"Genome Res"},{"key":"2022071906210992000_ref13","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/gkz096","article-title":"DriverML: a machine learning algorithm for identifying driver genes in cancer sequencing studies","volume":"47","author":"Han","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2022071906210992000_ref14","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1089\/cmb.2010.0265","article-title":"Algorithms for detecting significantly mutated pathways in cancer","volume":"18","author":"Vandin","year":"2011","journal-title":"J Comput Biol"},{"key":"2022071906210992000_ref15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/ng.3168","article-title":"Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes","volume":"47","author":"Leiserson","year":"2015","journal-title":"Nat Genet"},{"key":"2022071906210992000_ref16","doi-asserted-by":"crossref","first-page":"e1003460","DOI":"10.1371\/journal.pcbi.1003460","article-title":"VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data. Radivojac P (ed.)","volume":"10","author":"Jia","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"2022071906210992000_ref17","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1101\/gr.125567.111","article-title":"Mutual exclusivity analysis identifies oncogenic network modules","volume":"22","author":"Ciriello","year":"2012","journal-title":"Genome Res"},{"key":"2022071906210992000_ref18","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.cell.2010.11.013","article-title":"An integrated approach to uncover drivers of cancer","volume":"143","author":"Akavia","year":"2010","journal-title":"Cell"},{"key":"2022071906210992000_ref19","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1093\/bioinformatics\/btt471","article-title":"Discovering causal pathways linking genomic events to transcriptional states using tied diffusion through interacting events (TieDIE)","volume":"29","author":"Paull","year":"2013","journal-title":"Bioinformatics"},{"key":"2022071906210992000_ref20","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms9554","article-title":"Systematic analysis of somatic mutations impacting gene expression in 12 tumour types","volume":"6","author":"Ding","year":"2015","journal-title":"Nat Commun"},{"key":"2022071906210992000_ref21","doi-asserted-by":"crossref","first-page":"R124","DOI":"10.1186\/gb-2012-13-12-r124","article-title":"DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer","volume":"13","author":"Bashashati","year":"2012","journal-title":"Genome Biol"},{"key":"2022071906210992000_ref22","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.1093\/bioinformatics\/btv499","article-title":"DIGGIT: a Bioconductor package to infer genetic variants driving cellular phenotypes","volume":"31","author":"Alvarez","year":"2015","journal-title":"Bioinformatics"},{"key":"2022071906210992000_ref23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41467-019-13803-0","article-title":"Interpreting pathways to discover cancer driver genes with moonlight","volume":"11","author":"Colaprico","year":"2020","journal-title":"Nat Commun"},{"key":"2022071906210992000_ref24","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.cell.2018.02.060","article-title":"Comprehensive characterization of cancer driver genes and mutations","volume":"173","author":"Bailey","year":"2018","journal-title":"Cell"},{"key":"2022071906210992000_ref25","first-page":"68","article-title":"The cancer genome atlas (TCGA): an immeasurable source of knowledge","volume":"19","author":"Tomczak","year":"2015","journal-title":"Contemp Oncol (Pozn)"},{"key":"2022071906210992000_ref26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"2022071906210992000_ref27","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1101\/gr.221218.117","article-title":"HIT\u2019nDRIVE: patient-specific multidriver gene prioritization for precision oncology","volume":"27","author":"Shrestha","year":"2017","journal-title":"Genome Res"},{"key":"2022071906210992000_ref28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.celrep.2018.03.077","article-title":"Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers","volume":"23","author":"Peng","year":"2018","journal-title":"Cell Rep"},{"key":"2022071906210992000_ref29","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41586-021-03771-1","article-title":"In silico saturation mutagenesis of cancer genes","volume":"596","author":"Mui\u00f1os","year":"2021","journal-title":"Nat"},{"key":"2022071906210992000_ref30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41586-019-1186-3","article-title":"Next-generation characterization of the cancer cell line Encyclopedia","volume":"569","author":"Ghandi","year":"2019","journal-title":"Nature"},{"key":"2022071906210992000_ref31","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nature14129","article-title":"Comprehensive genomic characterization of head and neck squamous cell carcinomas","volume":"517","author":"Lawrence","year":"2015","journal-title":"Nature"},{"key":"2022071906210992000_ref32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrc.2018.11","article-title":"The molecular landscape of head and neck cancer","volume":"18","author":"Leemans","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"2022071906210992000_ref33","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s43018-019-0018-6","article-title":"Discovering the anticancer potential of non-oncology drugs by systematic viability profiling","volume":"1","author":"Corsello","year":"2020","journal-title":"Nat Cancer"},{"key":"2022071906210992000_ref34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2045-3701-2-19","article-title":"Regulation of triglyceride metabolism by glucocorticoid receptor","volume":"2","author":"Wang","year":"2012","journal-title":"Cell Biosci"},{"key":"2022071906210992000_ref35","doi-asserted-by":"crossref","first-page":"572981","DOI":"10.3389\/fendo.2020.572981","article-title":"Multifaceted control of GR Signaling and its impact on hepatic transcriptional networks and metabolism","volume":"11","author":"Pr\u00e6stholm","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2022071906210992000_ref36","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-1-4939-2895-8_6","article-title":"How do glucocorticoids regulate lipid metabolism?","volume":"872","author":"Guia","year":"2015","journal-title":"Adv Exp Med Biol"},{"key":"2022071906210992000_ref37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1530\/JOE-11-0135","article-title":"Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells","volume":"211","author":"Schlossmacher","year":"2011","journal-title":"J Endocrinol"},{"key":"2022071906210992000_ref38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2010.10.020","article-title":"Glucocorticoid receptor signaling and prostate cancer","volume":"302","author":"Kassi","year":"2011","journal-title":"Cancer Lett"},{"key":"2022071906210992000_ref39","first-page":"188","article-title":"Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments","volume":"3","author":"Sundahl","year":"2016","journal-title":"Onco Targets Ther"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/23\/4\/bbac280\/45017867\/bbac280.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/23\/4\/bbac280\/45017867\/bbac280.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T11:23:16Z","timestamp":1700824996000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbac280\/6634226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,9]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,7,18]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbac280","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,7,18]]},"published":{"date-parts":[[2022,7,9]]},"article-number":"bbac280"}}