Characterization and Clinical Significance of EIF1AX Mutations and Co-Mutations

Abstract

<p><strong>Objective</strong>. Mutations in the EIF1AX gene have been recently detected in a small percentage of benign and malignant thyroid lesions. We sought to investigate the prevalence and clinical significance of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution.</p><p><strong>Materials and Methods</strong>. A 5-year retrospective analysis was performed on thyroid nodules with a cytologic diagnosis of Bethesda category III or IV, which had undergone testing by our in-house next generation sequencing panel. Surgically resected nodules with EIF1AX mutations were identified, and mutation type and presence of co-mutations were correlated with histopathologic diagnosis.</p><p><strong>Results</strong>. 41/904 (4.5%) cases overall and 26/229 (11.4%) surgically resected nodules harbored an EIF1AX mutation. The most common histologic diagnoses were follicular thyroid carcinoma and follicular variant of papillary thyroid carcinoma. 11/26 (42.3%) of nodules had isolated EIF1AX mutation. Co- mutations were found in RAS (12/26; 46.2%), TERT (5/26; 19.2%) and TP53 (2/26; 7.7%). EIF1AX mutation alone conferred a 36.4% risk of malignancy (ROM) and 54.5% ROM or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), while the ROM was significantly higher in nodules with concurrent RAS (71.4%), TERT, TP53 and RAS+TERT (100%) mutations.</p><p><strong>Conclusion</strong>. EIF1AX mutations occur in benign and malignant follicular thyroid neoplasms. In our cohort, the majority of mutations occurred at the splice acceptor site between exons 5 and 6. Importantly, the coexistence of EIF1AX mutations with other driver pathogenic mutations in RAS, TERT and TP53 conferred a 100% ROM or NIFTP, indicating that such nodules require surgical removal.</p>

The prognostic power of gene mutations in thyroid cancer

“…More recently, three groups assessed the pattern of EIF1AX mutations in thyroid cancers. Gargano et al reported, in a series of surgically removed nodules, a risk of malignancy of 100% for specimens with EIF1AX mutations (most of them at A113splice) when coexisting with additional mutations (overwhelmingly at NRAS , HRAS , or KRAS ) ( 63 ). Karsogliu-French and colleagues evaluated 31 consecutive patients with EIF1AX mutations: the 18 specimens without coexisting mutations in RAS genes were enriched in benign disease (12/18 were FA, 3/18 hyperplastic nodules (HN) and 3/18 FTC), whereas the 13 EIF1AX + RAS samples showed primarily malignant phenotypes (6/13 PTC, 3/13 ATC, 2/13 NIFTP, 1/13 FA, and 1/13 HN) ( 64 ).…”