EIF1AX – Uveal Melanoma

Somatic mutations in EIF1AX have been recurrently identified in uveal melanoma (UM), particularly in tumors retaining both copies of chromosome 3 (disomy 3), a subgroup associated with lower metastatic risk. Initial exome sequencing of 31 disomy 3 tumors revealed EIF1AX mutations in 15 cases (48%) (PMID:23793026). Subsequent targeted studies confirmed EIF1AX alterations in 14 of 81 UM (17%) (PMID:27123562) and in 8 of 85 Chinese patients (9%) (PMID:31614358).

The EIF1AX variants are predominantly in‐frame N-terminal tail changes or splice‐site alterations, exemplified by the recurrent splice donor mutation c.429+1G>A. These mutations are almost mutually exclusive with BAP1 and SF3B1 alterations and show strong enrichment in disomy 3 tumors. Case–control analyses demonstrate that EIF1AX-mutant UM have a markedly lower rate of early metastasis (2/28 patients) and prolonged disease‐free survival compared with mutation‐negative counterparts (PMID:26923342).

Functional assays in yeast reveal that N-terminal tail substitutions (e.g., p.Arg13Pro) destabilize closed preinitiation complexes and heighten codon discrimination, suggesting altered translational initiation fidelity (PMID:29206102). In UM cell lines, knockdown of mutant EIF1AX impairs viability and shifts ribosome occupancy of translation machinery transcripts, indicating a potential gain-of-function that drives tumor cell survival (PMID:28594900).

Collectively, the high frequency of EIF1AX mutations in disomy 3 UM, consistent mutual exclusivity with other drivers, and concordant functional data support a Strong gene–disease association. Clinically, EIF1AX genotyping refines prognostic stratification, identifying a subset of UM patients with favorable outcomes and informing surveillance intensity.

References

• Nature Genetics • 2013 • Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3 PMID:23793026
• JAMA Ophthalmology • 2016 • Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes PMID:27123562
• eLife • 2017 • eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast PMID:29206102
• PLoS One • 2017 • Systematic genomic and translational efficiency studies of uveal melanoma PMID:28594900

Evidence Based Scoring (AI generated)