How does an EIF1AX mutation at a splice site contribute to cancer development?

EIF1AX Splice Site Mutations and Their Role in Cancer Development

EIF1AX splice site mutations contribute to cancer development through aberrant mRNA processing and protein function, with their oncogenic potential significantly enhanced when they co-occur with other driver mutations, particularly RAS, TERT, and TP53 mutations. 1

Mechanism of EIF1AX Splice Site Mutations in Oncogenesis

Molecular Alterations

• EIF1AX (Eukaryotic Translation Initiation Factor 1A X-Linked) mutations primarily occur at two hotspots:
  • Exon 2 mutations (affecting amino acids near the N-terminus)
  • Intron 5/exon 6 splice site mutations (most commonly A113_splice) 2

Functional Consequences

• Splice site mutations disrupt normal mRNA processing, leading to:
  1. Aberrant splicing patterns
  2. Unbalanced ratio of various mRNA isoforms
  3. Altered protein function affecting translation initiation 1

Oncogenic Transformation

• EIF1AX splice site mutations alone have limited oncogenic potential (~13-36% cancer risk) 3, 4
• Oncogenic potency dramatically increases with co-mutations:
  • EIF1AX + RAS: 71-80% cancer risk
  • EIF1AX + RAS + TERT/TP53: Nearly 100% cancer risk, often resulting in aggressive cancers 3, 5

Clinical and Pathological Significance

Cancer Types Associated with EIF1AX Mutations

• Thyroid cancers:
  • Papillary thyroid carcinoma (PTC), especially follicular variant
  • Anaplastic thyroid carcinoma (ATC) when co-occurring with other mutations
  • Follicular thyroid carcinoma 2, 4
• Metanephric adenoma with sarcomatoid features 1

Mutation Patterns and Cancer Progression

• Isolated EIF1AX mutations are often found in benign lesions or low-grade malignancies
• The A113_splice mutation at the intron 5/exon 6 junction is particularly associated with malignancy 2
• Progressive accumulation of additional mutations correlates with increasing malignant potential:
  • EIF1AX mutation alone: Predominantly benign (88%)
  • EIF1AX + one additional mutation: Mixed benign/malignant profile
  • EIF1AX + ≥2 additional mutations: 100% malignant 5

Specific Role in Cancer Progression

• In thyroid cancer, the p.Ala113_splice mutation appears specifically in poorly differentiated components but not in well-differentiated areas of the same tumor, suggesting its role in cancer progression rather than initiation 6
• Different EIF1AX mutations may have distinct phenotypic effects:
  • p.Ala113_splice: Associated with tumor progression
  • p.Gly6_splice: Not clearly linked to dedifferentiation 6

Diagnostic and Clinical Implications

Molecular Testing Considerations

• EIF1AX mutations should be evaluated in the context of co-occurring genetic alterations 1
• Splice site variants up to -16 position at splice acceptor sites and +5 position at donor sites should be assessed for splicing defects 1
• MutSpliceDB (https://brb.nci.nih.gov/splicing) provides RNA-seq evidence for splice site variant effects 1

Risk Assessment

• When detected in preoperative samples:
  • Isolated non-splice EIF1AX mutations: Low risk of malignancy
  • Isolated splice site mutations: ~33% risk of malignancy
  • Co-occurring mutations (especially with RAS, TERT, or TP53): High risk of malignancy 3, 4

Management Implications

• Thyroid nodules with isolated EIF1AX mutations may warrant close monitoring rather than immediate surgery
• Nodules with EIF1AX mutations plus additional alterations (especially RAS, TERT, or TP53) require surgical management due to high malignancy risk 3, 4

Common Pitfalls and Caveats

• Misinterpreting isolated EIF1AX mutations as definitively malignant
• Failing to assess for co-occurring mutations that significantly increase cancer risk
• Not distinguishing between different types of EIF1AX mutations (splice site vs. non-splice)
• Overlooking the importance of specific splice site locations in determining oncogenic potential

EIF1AX mutations represent an important but complex genetic alteration in cancer development, with their oncogenic potential heavily dependent on mutation type and co-occurring genetic alterations. Understanding these nuances is crucial for accurate risk assessment and appropriate clinical management.