Frequency and Clinical Impact of <em>BRAF</em> and <em>RAS</em> Mutations in Follicular Variant Papillary Thyroid Carcinoma

<strong>Background and aims: </strong>Inconsistent findings have been reported regarding the frequency and clinical impact of <em>BRAF</em> and <em>RAS</em> mutations in Follicular Variant Papillary Thyroid Carcinoma (FVPTC). <strong>Materials and methods: </strong>We systematically searched the PubMed and Embase libraries and The Cancer Genome Atlas Program (TCGA) and The International Cancer Genome Consortium (ICGC) databases. One part focused on the frequency distribution of <em>BRAF</em> and <em>RAS</em> gene mutations in FVPTC and its various histological subtypes, while another explored their clinical associations. <strong>Results:</strong> Our meta-analysis comprised a large sample size of 10,902 FVPTC patients, including 2,370 cases with relevant mutation-related clinical information. The overall mutation rates for <em>BRAF</em> and <em>RAS</em> in FVPTC were found to be 19.9% and 35.3%, with the highest incidence of <em>BRAF</em> (31.0%) and <em>RAS</em> (37.5%) mutations observed in invasive FVPTC and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), respectively. No significant gender or age differences were documented between patients with mutated versus wild-type FVPTCs. In comparison to wild-type patients, those with <em>BRAF</em> mutations were significantly associated with tumor multifocality (OR 1.65; 95% CI, 1.21-2.25; P&lt;0.01), extrathyroidal extension (OR 2.82; 95% CI, 1.61-4.94; P&lt;0.01), lymph node metastasis (OR 2.41; 95% CI, 1.49-3.91; P&lt;0.01), advanced TNM stage (OR 3.11; 95% CI, 2.03-4.78; P&lt;0.01), and tumor recurrence (OR 3.42; 95% CI, 1.86-6.28; P&lt;0.01). Conversely, no significant associations were identified in patients with <em>RAS</em> mutations. <strong>Conclusion: </strong>As highlighted by our meta-analysis, <em>RAS</em> mutations were found to be more prevalent in FVPTC than <em>BRAF</em> mutations. Interestingly, while the frequency of <em>BRAF</em> mutations was higher in invasive subtypes, benign exhibited the opposite trend with<em> RAS</em> mutations being more commonly identified. Furthermore, we also noted that FVPTC patients with <em>BRAF</em> mutations had a higher risk of poor clinical outcomes, while <em>RAS</em> mutations did not show similar associations. <strong>Keywords: </strong>Follicular Variant Papillary Thyroid Carcinoma, <em>BRAF, RAS,</em> Frequency, Histology, Clinical feature, Meta-Analysis