The role of EIF1AX in thyroid cancer tumourigenesis and progression

Simões‐Pereira, Joana; Moura, M. M.; Marques, Inês J.; Rito, Miguel; Cabrera, Rafael; Leite, Valeriano; Cavaco, Branca

doi:10.1007/s40618-018-0919-8

Cited by 19 publications

(18 citation statements)

References 11 publications

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“…Co-occurrence of EIF1AX and H/N/K-RAS mutations is correlated with tumor aggressiveness, especially when it is the A113_splice mutations for EIF1AX gene [15, 25]. That is consistent with our results that EIF1AX mutations in FTC were located at intron 5/exon 6, correlated with advanced disease, and coexisted with NRAS mutation.…”

Section: Discussionsupporting

confidence: 90%

“…2. In order to have an overall understanding of EIF1AX mutation detected in thyroid tumors, we also analyzed the occurrence of EIF1AX mutations in the COSMIC database [23], cBioPortal for cancer genomics database [24] and previous studies [14, 15, 25–29] (Table 2). EIF1AX intron5/exon6 mutations occurred in benign or malignant thyroid tumors.…”

Section: Resultsmentioning

confidence: 99%

“…EIF1AX mutations were strikingly enriched in poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) and predicted for shorter survival in PDTC [14]. Distinct mutations on EIF1AX may be correlated with different tumor phenotypes [15]. However, the role of TERTp or EIF1AX mutations in follicular thyroid tumors hadn’t been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

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Mutation profiles of follicular thyroid tumors by targeted sequencing

et al. 2019

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Background One of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant. We aimed to characterize the mutational profiles of follicular thyroid tumor and to identify markers with potential diagnostic and prognostic implications. Methods Targeted sequencing with a panel of 18 thyroid cancer-related genes was performed on 48 tissue samples from follicular thyroid adenoma (FTA), 32 follicular tumors of uncertain malignant potential (FT-UMP), 17 well-differentiated tumors of uncertain malignant potential (WDT-UMP) and 53 samples from follicular thyroid carcinoma (FTC). The correlation of mutation profiles and clinicopathological features and prognosis were also analyzed. Results We identified 95 nonsilent mutations spanning 14 genes. Specifically, TERT promoter (TERTp) mutations were exclusively detected in FTC. A total of 80% EIF1AX exon 2 mutations (4/5) and 75% TSHR mutations (3/4) occurred in FTA, whereas the rest of them occurred in FT-UMP. KRAS mutations and TP53 mutations were only presented in borderline or malignant tumors. H/N-RAS mutations were detected in all four subtypes, but were most commonly found in WDT-UMP ( p = 0.031). All N-RAS mutations were located at codon 61. BRAF V600E and RET fusion were absent in the entire cohort. In FTC cases, EIF1AX mutations were all located at intron 5/exon 6 and correlated with advanced disease ( p = 0.032). Both EIF1AX and TERTp mutations predicted shorter disease-free survival ( p = 0.007, p = 0.024, respectively). Further analysis revealed that TERTp mutations were correlated with shorter disease-free survival in patients with minimally invasive /encapsulated angioinvasive FTC ( p = 0.017), but not in those with widely invasive FTC ( p = 0.297). Conclusion TERTp , EIF1AX, TSHR, H/N/K-RAS and TP53 mutations may have diagnostic or prognostic potential in follicular thyroid tumors. TERTp mutations may predict a poor outcome in patients with minimally invasive/encapsulated angioinvasive FTC.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutation profiles of follicular thyroid tumors by targeted sequencing

et al. 2019

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“…Similar to other studies, the most common type of EIF1AX mutation identified in our study was the A113_splice mutation at the intron 5/exon 6 splice site of EIF1AX (17/26), followed by the missense mutations in N-terminus of the protein (5/26). Previous studies have concluded that the A113_splice mutation, especially with co-existing RAS mutation, is more frequently observed in thyroid cancer than isolated EIF1AX mutations or mutations at the N-terminus hotspot of the gene (4,11,14). In our study, 13/17 (76.5%) surgically resected nodules with the A113_splice mutation and 3/5 (60%) nodules with an N-terminal missense mutation were malignant.…”

Section: Discussionsupporting

confidence: 43%

“…Originally identified in uveal melanomas, EIF1AX mutations have now also been detected in a variety of other tumor types, including low-grade gliomas, lung adenocarcinoma, endometrial carcinoma, and various neoplastic and nonneoplastic thyroid lesions (4,(9)(10)(11). Missense mutations of the first 2-15 amino acids at the N-terminus of EIFIAX have been identified in several cancers (9,(12)(13)(14). An additional hotspot splice-site mutation (A113_ splice) in the C-terminus of the protein is thought to be exclusive to thyroid carcinoma (9,11,15).…”

Section: Discussionmentioning

confidence: 99%

Characterization and Clinical Significance of EIF1AX Mutations and Co-Mutations

Gargano

Badjatia

Nikolaus

et al. 2021

ama

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Objective. 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.Materials and Methods. 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.Results. 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.Conclusion. 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.

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