Comparative Analysis of Pathological Characteristics and Prognostic Outcomes in Malignant Thyroid Tumors with Single and Co-existing <i>RAS</i> Mutations

Background: The implications of RAS mutations in malignant thyroid tumors are under scrutiny, focusing on prevalence, clinicopathological features, and prognosis. Methods: Centers include patients with malignant thyroid tumors from the TCGA, ICGC, MSKCC, and a multi-center thyroid cancer cohort in China. Pubmed/MEDLINE and Embase libraries were included in the systematic review. The differences in demography, clinical pathology, and prognosis of four distinct mutation groups ("non-mutation, single RAS mutation, driver mutation, and RAS co-mutation") were analyzed. Results: 21,370 patients with thyroid tumors who underwent RAS mutation testing were included. The overall frequency of RAS mutations was 19.34% (NRAS:12.94%&gt;HRAS:6.61%&gt;KRAS:5.00%). RAS co-mutations were more prevalent in tumors with lower differentiation levels. Importantly, RAS co-mutation, but not single RAS mutation increased the risk of Distant Metastasis (OR=12.28; 95%CI,3.19-47.25; P&lt;0.001), Advanced AJCC Stage (OR=4.60; 95%CI,1.91-11.08; P=0.001), Overall Survival (OS) (HR=2.90; 95%CI,1.63-5.13; P&lt;0.001), and Progression-free Survival (PFS) (HR=6.77; 95%CI,6.77-18.87; P&lt;0.001) compared with the non-mutation group. We also found the driver mutation group exhibited a higher risk of Extrathyroidal Extension, Advanced Tumor Stage, Lymph Node Metastasis, Distant Metastasis, Advanced AJCC Stage, OS, and PFS. Conclusions: RAS co-mutations might be the main contributor to malignant clinicopathological characteristics or prognosis, single RAS mutation not.