{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:13:07Z","timestamp":1793128387851,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>In light of the development of RAS inhibitors, a reliable assessment of the prevalence of RAS mutations and their correlation with the clinical features of patients with HNC is crucially needed. This meta-analysis compiles the findings of 149 studies with over 8500 HNC patients and assesses the global prevalence of mutations in the HRAS, KRAS and NRAS genes. The available data were stratified according to geographical region, clinical features, and tumor characteristics, including human papillomavirus (HPV) infection status and tumor stage. In addition, the distribution of codon substitutions in each RAS gene was assessed. The estimated mutation rate is highest for HRAS (7%), followed by KRAS (2.89%) and NRAS (2.20%). HRAS prevalence in South Asia (15.28%) is twice as high as the global estimate. HRAS mutations are more prevalent in oral cavity and salivary gland tumors. In contrast, KRAS mutations are found more frequently in sinonasal tumors, and NRAS mutations are found chiefly in tumors of the nasopharynx. OR analyses show a significant association between HRAS mutations and a high tumor stage (OR=3.63). In addition, there is a significant association between HPV-positive status and KRAS mutations (OR=2.09). This study highlights RAS as a potential therapeutic target in certain subsets of HNC patients.<\/jats:p>","DOI":"10.3389\/fonc.2022.838911","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T06:40:13Z","timestamp":1651819213000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Worldwide Prevalence and Clinical Characteristics of RAS Mutations in Head and Neck Cancer: A Systematic Review and Meta-Analysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Ofra","family":"Novoplansky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sankar","family":"Jagadeeshan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohad","family":"Regev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idan","family":"Menashe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Elkabets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1056\/NEJMRA1715715","article-title":"Head and Neck Cancer","volume":"382","author":"Chow","year":"2020","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.21101\/cejph.a5565","article-title":"Environmental and Behavioural Head and Neck Cancer Risk Factors","volume":"27","author":"Boras","year":"2019","journal-title":"Cent Eur J Public Health"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1038\/nrc.2018.11","article-title":"The Molecular Landscape of Head and Neck Cancer","author":"Leemans","year":"2018"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1208130","article-title":"The Mutational Landscape of Head and Neck Squamous Cell Carcinoma","volume":"333","author":"Stransky","year":"2011","journal-title":"Science (80- )"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2017.06.009","article-title":"RAS Proteins and Their Regulators in Human Disease","volume":"170","author":"Simanshu","year":"2017","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1042\/BST20180173","article-title":"RAS Variant Signalling","volume":"46","author":"Mo","year":"2018","journal-title":"Biochem Soc Trans"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3682","article-title":"The Frequency of Ras Mutations in Cancer","volume":"80","author":"Prior","year":"2020","journal-title":"Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13045-021-01127-w","article-title":"Emerging Strategies to Target RAS Signaling in Human Cancer Therapy","volume":"14","author":"Chen","year":"2021","journal-title":"J Hematol Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2103695","article-title":"Sotorasib for Lung Cancers With KRAS P.G12C Mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33036","article-title":"Tipifarnib in Recurrent, Metastatic HRAS-Mutant Salivary Gland Cancer","volume":"126","author":"Hanna","year":"2020","journal-title":"Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02903","article-title":"Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations","volume":"39","author":"Ho","year":"2021","journal-title":"J Clin Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PMED.1000097","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"6","author":"Moher","year":"2009","journal-title":"PloS Med"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.46658\/JBIMES-20-01","article-title":"JBI Manual for Evidence Synthesis","volume-title":"JBI","author":"Aromataris","year":"2020"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in Meta-Analysis Detected by a Simple, Graphical Test","volume":"315","author":"Egger","year":"1997","journal-title":"Br Med J"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting Meta-Analyses in R With the Metafor","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/ebmental-2019-300117","article-title":"How to Perform a Meta-Analysis With R: A Practical Tutorial","volume":"22","author":"Balduzzi","year":"2019","journal-title":"Evid Based Ment Health"},{"key":"B19","volume-title":"How to Conduct a Meta-Analysis of Proportions in R : A Comprehensive Tutorial Conducting Meta-Analyses of Proportions in R","author":"Wang","year":"2018"},{"key":"B20","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1093\/ANNONC\/MDZ084","article-title":"Head and Neck Cancer Prevention: From Primary Prevention to Impact of Clinicians on Reducing Burden","volume":"30","author":"Hashim","year":"2019","journal-title":"Ann Oncol"},{"key":"B21","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":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8111896","article-title":"Comprehensive Genomic Review of TCGA Head and Neck Squamous Cell Carcinomas (HNSCC)","volume":"8","author":"Say\u00e1ns","year":"2019","journal-title":"J Clin Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/J.ORALONCOLOGY.2014.01.016","article-title":"International Trends in Head and Neck\u00a0Cancer Incidence Rates: Differences by Country, Sex and Anatomic Site","volume":"50","author":"Simard","year":"2014","journal-title":"Oral Oncol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/S1368-8375(99)00058-5","article-title":"Ras Gene Mutations in Oral Cancer in Eastern India","volume":"36","author":"Das","year":"2000","journal-title":"Oral Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1991.133","article-title":"High Frequency Mutation in Codons 12 and 61 of H-Ras Oncogene in Chewing Tobacco-Related Human Oral Carcinoma in India","volume":"63","author":"Saranath","year":"1991","journal-title":"Br J Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/0964-1955(95)00065-8","article-title":"Molecular Changes in Oral Cancer may Reflect Aetiology and Ethnic Origin","volume":"32","author":"Paterson","year":"1996","journal-title":"Eur J Cancer Part B Oral Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910480318","article-title":"Ras Mutations in United Kingdom Examples of Oral Malignancies Are Infrequent","volume":"48","author":"Chang","year":"1991","journal-title":"Int J Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/IJC.11265","article-title":"Bidi Smoking and Oral Cancer: A Meta-Analysis","volume":"106","author":"Rahman","year":"2003","journal-title":"Int J Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2010.01785.x","article-title":"Oral Cavity Cancer Risk in Relation to Tobacco Chewing and Bidi Smoking Among Men in Karunagappally, Kerala, India: Karunagappally Cohort Study","volume":"102","author":"Jayalekshmi","year":"2011","journal-title":"Cancer Sci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4103\/0971-5851.133702","article-title":"A Review of the Systemic Adverse Effects of Areca Nut or Betel Nut","volume":"35","author":"Garg","year":"2014","journal-title":"Indian J Med Paediatr Oncol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/J.CANEP.2017.09.003","article-title":"Associations Between Oral Hygiene Habits, Diet, Tobacco and Alcohol and Risk of Oral Cancer: A Case\u2013Control Study From India","volume":"51","author":"Gupta","year":"2017","journal-title":"Cancer Epidemiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/22.9.1497","article-title":"Characteristics of Mutations in the P53 Gene in Oral Squamous Cell Carcinoma Associated With Betel Quid Chewing and Cigarette Smoking in Taiwanese G : C to A : T Transitions Were the Predominant Mutations Still Showed an Independent Effect on G : C to A","volume":"22","author":"Hsieh","year":"2001","journal-title":"Carcinogenesis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4274(00)00262-9","article-title":"Synergistic Effects of Peroxynitrite on Arecoline-Induced Cytotoxicity in Human Buccal Mucosal Fibroblasts","volume":"118","author":"Chang","year":"2000","journal-title":"Toxicol Lett"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1038\/ncomms3873","article-title":"Mutational Landscape of Gingivo-Buccal Oral Squamous Cell Carcinoma Reveals New Recurrently-Mutated Genes and Molecular Subgroups","volume":"4","year":"2013","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/J.1365-2362.2006.01621.X","article-title":"Interaction Between Cigarette, Alcohol and Betel Nut Use on Esophageal Cancer Risk in Taiwan","volume":"36","author":"Wu","year":"2006","journal-title":"Eur J Clin Invest"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001258","article-title":"Diagnostic Significance of HRAS Mutations in Epithelial-Myoepithelial Carcinomas Exhibiting a Broad Histopathologic Spectrum","volume":"43","author":"Urano","year":"2019","journal-title":"Am J Surg Pathol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S58791","article-title":"Oncogene Mutational Profile in Nasopharyngeal Carcinoma","volume":"7","author":"Zhang","year":"2014","journal-title":"Onco Targets Ther"},{"key":"B38","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1158\/1078-0432.CCR-13-3310","article-title":"Integrative and Comparative Genomic Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas","volume":"21","author":"Seiwert","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11762","article-title":"Clues Toward Precision Medicine in Oral Squamous Cell Carcinoma: Utility of Next-Generation Sequencing for the Prognostic Stratification of High-Risk Patients Harboring Neck Lymph Node Extracapsular Extension","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3741","article-title":"Mutation Patterns in Recurrent and\/or Metastatic Oropharyngeal Squamous Cell Carcinomas in Relation to Human Papillomavirus Status","volume":"10","author":"Reder","year":"2021","journal-title":"Cancer Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800948","article-title":"H-Ras Mutation Modulates the Expression of Major Cell Cycle Regulatory Proteins and Disease Prognosis in Oral Carcinoma","volume":"20","author":"Sathyan","year":"2007","journal-title":"Mod Pathol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS14035170","article-title":"EGFR Expression and KRAS and BRAF Mutational Status in Intestinal-Type Sinonasal Adenocarcinoma","volume":"14","author":"Szablewski","year":"2013","journal-title":"Int J Mol Sci"},{"key":"B43","article-title":"Mutational Analysis of K-Ras and Ras Protein Expression in Larynx Squamous Cell Carcinoma","volume":"25","author":"Ru\u00edz-Godoy","year":"2006","journal-title":"J Exp Clin Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/J.EJCA.2016.01.003","article-title":"Targeted Next-Generation Sequencing of Locally Advanced Squamous Cell Carcinomas of the Head and Neck Reveals Druggable Targets for Improving Adjuvant Chemoradiation","volume":"57","author":"Tinhofer","year":"2016","journal-title":"Eur J Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.251","article-title":"Impaired PTPN13 Phosphatase Activity in Spontaneous or HPV-Induced Squamous Cell Carcinomas Potentiates Oncogene Signaling Through the MAP Kinase Pathway","volume":"28","author":"Hoover","year":"2009","journal-title":"Oncogene"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/172460080502000409","article-title":"Human Papillomavirus (HPV) Typing in Relation to Ras Oncogene mRNA Expression in HPV-Associated Human Squamous Cervical Neoplasia","volume":"20","author":"Mammas","year":"2005","journal-title":"Int J Biol Markers"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgs104","article-title":"A Critical Role of MYC for Transformation of Human Cells by HPV16 E6E7 and Oncogenic HRAS","volume":"33","author":"Narisawa-Saito","year":"2012","journal-title":"Carcinogenesis"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.157","article-title":"Frequent KRAS and HRAS Mutations in Squamous Cell Papillomas of the Head and Neck","volume":"6","author":"Sasaki","year":"2020","journal-title":"J Pathol Clin Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.838911\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T06:40:19Z","timestamp":1651819219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.838911\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,6]]},"references-count":48,"alternative-id":["10.3389\/fonc.2022.838911"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.838911","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.11.30.21267087","asserted-by":"object"}]},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,6]]},"article-number":"838911"}}