Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules

Abstract

The EIF1AX gene 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 occurence of EIF1AX mutations 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 FNA samples with indeterminate cytology were analyzed. Using surgically removed samples, EIF1AX mutations 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 5 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 of EIF1AX was the most common. All 4 carcinomas harbored A113_splice mutation and three of them had one or more coexisting mutations, typically RAS. All PTC carrying EIF1AX mutation were encapsulated follicular variants. In summary, this study shows that EIF1AX mutations 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, EIF1AX mutations confer ~20% risk of cancer; the risk is likely to be higher in nodules carrying a A113_splice mutation and when EIF1AX co-exists with RAS mutations.

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

“…All 22 Hürthle cell carcinomas tested were negative for EIF1Ax mutation. 26 In our study, the one EIF1AX-mutated case with surgical follow-up displayed a Hürthle cell adenoma. The displayed a Hürthle cell adenoma and NIFTP on histology.…”

“…EIF1Ax mutations may also coexist with other mutations such as RAS or TP53, which is more common in malignant nodules. All 22 Hürthle cell carcinomas tested were negative for EIF1Ax mutation . In our study, the one EIF1AX‐mutated case with surgical follow‐up displayed a Hürthle cell adenoma.…”

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

“…PAX8/PPARG rearrangements occur in approximately 8% of FA, 10% of NIFTP, 1% of follicular variant PTC and 20–30% of FTC. EIF1AX mutation can be found in hyperplastic nodules, FA, NIFTP, FTC, PTC, PDC, ATC and Hürthle cell carcinomas . Cytogenetic changes occur in 50% of FA and 65% of FTC .…”

“…EIF1AX mutation can be found in hyperplastic nodules, FA, NIFTP, FTC, PTC, PDC, ATC and H€ urthle cell carcinomas. 90,[199][200][201][202] Cytogenetic changes occur in 50% of FA and 65% of FTC. 1 PTEN and PIK3CA mutations also occur in 5% of FA and up to 10% of FTC.…”

Next-generation sequencing in thyroid cancer

“…In the conventional type FCs, NRAS was the most frequently affected gene, followed by TSHR and KRAS . TP53 was the most commonly mutated gene in the oncocytic type FCs, followed by HRAS , KRAS , and PTEN [19]. …”