Meta-Analysis of the <em>RAS</em> Mutation and Co-mutation in Thyroid Neoplasms: A Multicenter Study and Systematic Review.

<strong>Background: </strong>The prevalence, clinicopathological characteristics, and prognostic implications of <em>RAS</em> mutations and co-mutations in thyroid neoplasms remain subjects of controversy. <strong>Methods:</strong> Multicenter, systematic review and meta-analysis were applied. Centers include patients with thyroid neoplasms from the TCGA, ICGC, MSKCC, and a multi-center thyroid cancer cohort in China. Pubmed/MEDLINE and Embase libraries were included in Systematic review. The frequency distribution of <em>RAS</em> mutations and co-mutations was described. Additionally, the differences in demography, clinical-pathology, and prognosis of four distinct mutation groups ("non-mutation, single<em> RAS</em> mutation, driver mutation, and <em>RAS</em> co-mutation") were analyzed. <strong>Results:</strong> 21,370 patients with thyroid neoplasms who underwent <em>RAS</em> mutation testing were included. The overall frequency of <em>RAS</em> mutations was 19.34% (<em>NRAS</em>:12.94%&gt;<em>HRAS</em>:6.61%&gt;<em>KRAS</em>:5.00%). Among different histological types, <em>RAS</em> mutations had the highest mutation rate in follicular thyroid carcinoma (30.83%). And<em> RAS</em> co-mutations were more prevalent in tumors with lower differentiation levels. Importantly, <em>RAS</em> co-mutation, but not single <em>RAS</em> mutation significantly increased the risk of Distant Metastasis (OR=8.00; <em>P</em>&lt;.001), Advanced AJCC Stage (OR=3.32; <em>P</em>=.02), Overall Survival (OS) (HR=2.99; <em>P</em>&lt;.001), and Progression-free Survival (PFS) (HR=6.77; <em>P</em>&lt;.001) compared with the non-mutation group. In addition, we also found the driver mutation group exhibited a higher risk of Advanced Tumor Stage (OR=1.55; <em>P</em>=.02), Lymph Node Metastasis (OR=1.77; <em>P</em>=.02), Distant Metastasis (OR=3.00; <em>P</em>=.04), Advanced AJCC Stage (OR=1.78; <em>P</em>=.005), OS (HR=1.92; <em>P</em>=.02), and PFS (HR=1.79; <em>P</em>=.03). <strong>Conclusions: </strong><em>RAS </em>co-mutations were the main contributor to malignant clinicopathological characteristics or prognosis, single <em>RAS </em>mutation not. These findings have important implications for identifying high-risk patients and implementing personalized treatment strategies. <strong>Keywords: </strong><em>RAS</em>; thyroid neoplasms; Frequency; Clinical-pathological; Prognosis