Worldwide Prevalence and Clinical Characteristics of RAS Mutations in Head and Neck Cancer: A Systematic Review and Meta-Analysis
Authors: Novoplansky Ofra , Jagadeeshan Sankar , Regev Ohad , Menashe Idan , Elkabets Moshe 
Published: December 2021

AbstractImportanceThere is considerable variation among different studies for the prevalence of RAS mutations in head and neck cancer (HNC) patients. 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.ObjectiveTo assess the worldwide prevalence of HRAS, KRAS, and NRAS mutations in HNC in the relation to geographical region, anatomical site(s) of the tumor(s) and clinical features.Data SourcesA systematic search of the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed to identify studies published since January 2000. Data were analyzed between June and September 2021.Study SelectionStudies that included mutational analyses of at least one of the target genes and reported the prevalence and frequency of mutations as an outcome measure were included. Studies including less than ten patients or were conducted before year 2000 were excluded.Data Extraction and SynthesisTwo researchers independently reviewed the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Random-effects models were applied to results with high heterogeneity. Otherwise, fixed-effects models were used for the analyses. Dichotomous variables were pooled as odds ratios (OR).Main Outcome(s) and Measure(s)The primary outcome was mutation prevalence. Secondary outcomes included the location of the mutated codon and amino acid substitution.ResultsThe 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).Conclusions and RelevanceRAS mutations occur in a subset of HNC patients and their prevalence varies according to geography, tumor’s anatomical site, stage, and HPV status. This meta-analysis provides support for their potential as viable therapeutic targets in HNC patients.Key PointsQuestionWhat is the prevalence of mutations in RAS genes in head and neck cancer (HNC) with respect to anatomical site, geographical region, and clinical features?FindingsThis 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 prevalence of RAS mutations varies between the seven major anatomical sites of HNC. The HRAS mutation rate in South Asia is double that in other geographical regions. Mutations in HRAS are associated with advanced disease, and mutations in KRAS are positively associated with HPV status.MeaningThis study presents the most comprehensive assessment of the prevalence of RAS mutations in HNC and their correlation with geographical regions and with clinical features.