What are the effects of an eIF1AF splice site mutation on thyroid cells?

EIF1AX Splice Site Mutations in Thyroid Cells: Implications and Clinical Significance

EIF1AX splice site mutations are genetic alterations that occur in thyroid cells with significant implications for cancer development, particularly when co-occurring with other mutations, and are associated with both benign and malignant thyroid neoplasms.

Understanding EIF1AX Mutations in Thyroid Cells

EIF1AX (Eukaryotic Translation Initiation Factor 1A X-Linked) is a gene that has been identified in the molecular pathogenesis of thyroid neoplasms. Mutations in this gene have been recognized in the WHO classification of differentiated follicular-derived thyroid carcinomas 1.

Key characteristics of EIF1AX mutations in thyroid cells include:

• Mutation Hotspots: EIF1AX mutations primarily occur in two regions:

  • The most common is the A113_splice mutation at the intron 5/exon 6 splice site (approximately 45% of cases) 2
  • A cluster of mutations in exon 2 (approximately 55% of cases) 3, 2

• Prevalence: EIF1AX mutations are found in approximately 4.5% of cytologically indeterminate thyroid nodules overall 4

• Distribution across thyroid pathologies:

  • Papillary thyroid carcinoma (PTC): 2.3%
  • Anaplastic thyroid carcinoma (ATC): 25%
  • Follicular adenomas: 7.4%
  • Hyperplastic nodules: 1.3% 3

Clinical Significance and Cancer Risk

The clinical significance of EIF1AX mutations varies significantly depending on:

1. Type of mutation: Splice site mutations carry higher malignancy risk than non-splice mutations

   • Splice-site mutations: 64% cancer risk
   • Non-splice mutations: 29% cancer risk 2

2. Presence of co-mutations: This is perhaps the most critical factor in determining malignancy risk

   • Isolated EIF1AX mutation: 36.4% risk of malignancy 4, with isolated non-splice mutations showing even lower risk 2
   • EIF1AX + RAS co-mutation: 71.4% risk of malignancy 4
   • EIF1AX + TERT, TP53, or RAS+TERT co-mutations: 100% risk of malignancy 4
   • All nodules with EIF1AX mutation and ≥2 additional molecular alterations were malignant (100%) 5

3. Histological associations:

   • When malignant, EIF1AX mutations are commonly found in:
     • Follicular variant of papillary thyroid carcinoma
     • Follicular thyroid carcinoma
     • Anaplastic thyroid carcinoma (especially with multiple co-mutations) 4, 5, 2
   • EIF1AX mutations have also been reported in Hürthle cell carcinoma 6

Molecular Pathways and Interactions

EIF1AX mutations appear to have important interactions with other molecular alterations in thyroid cancer:

• RAS pathway: EIF1AX mutations frequently co-occur with RAS mutations, suggesting potential synergistic effects in thyroid tumorigenesis 3, 2

• High-grade transformation: When EIF1AX mutations co-occur with TERT promoter and TP53 mutations, they are associated with anaplastic thyroid carcinoma and high-grade follicular cell-derived non-anaplastic carcinomas 5

• Molecular classification: EIF1AX is listed alongside other molecular markers (BRAF, RAS, TERT, etc.) in the WHO classification of differentiated follicular-derived thyroid carcinomas 1, 7

Clinical Management Implications

For thyroid nodules with detected EIF1AX mutations:

• Risk stratification should be based on:

  1. The specific type of EIF1AX mutation (splice site vs. non-splice)
  2. Presence of co-mutations (particularly RAS, TERT, and TP53)
  3. Clinical and ultrasound features of the nodule

• Management recommendations:

  • Isolated non-splice EIF1AX mutations: Lower risk of malignancy, may warrant observation in appropriate clinical context
  • Splice site EIF1AX mutations: Higher risk of malignancy, surgical consideration may be appropriate
  • EIF1AX mutations with co-mutations (especially RAS, TERT, or TP53): Significantly higher risk of malignancy, surgical management typically indicated 4, 2

Conclusion

EIF1AX splice site mutations represent an important molecular alteration in thyroid cells with implications for both benign and malignant neoplasms. The risk of malignancy increases significantly when these mutations co-occur with other genetic alterations, particularly RAS, TERT, and TP53 mutations. Understanding the specific type of EIF1AX mutation and its molecular context is crucial for appropriate risk stratification and clinical management of thyroid nodules harboring these genetic changes.