Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules

TheEIF1AXgene mutations have been recently found in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). The prevalence of these mutations in other types of thyroid cancers and benign nodules is unknown. In this study, we analyzed the occurrence ofEIF1AXmutations in exons 2, 5, and 6 of the gene in a series of 266 thyroid tumors and hyperplastic nodules by either Sanger or next-generation sequencing (ThyroSeq v.2). In addition, 647 thyroid fine-needle aspiration (FNA) samples with indeterminate cytology were analyzed. Using surgically removed samples,EIF1AXmutations were detected in 3/86 (2.3%) PTC, 1/4 (25%) ATC, 0/53 follicular carcinomas, 0/12 medullary carcinomas, 2/27 (7.4%) follicular adenomas, and 1/80 (1.3%) hyperplastic nodules. Among five mutation-positive FNA samples with surgical follow-up, one nodule was PTC and others were benign follicular adenomas or hyperplastic nodules. Overall, among 33 mutations identified, A113_splice mutation at the intron 5/exon 6 splice site ofEIF1AXwas the most common. All four carcinomas harbored A113_splice mutation and three of them had one or more coexisting mutations, typicallyRAS. All PTC carryingEIF1AXmutations were encapsulated follicular variants. In summary, this study shows thatEIF1AXmutations occur not only in thyroid carcinomas, but also in benign nodules. The most common mutation hotspot is the A113_splice, followed by a cluster of mutations in exon 2. When found in thyroid FNA samples,EIF1AXmutations confer ~20% risk of cancer; the risk is likely to be higher in nodules carrying a A113_splice mutation and whenEIF1AXcoexists withRASmutations.