RET Gene Alterations in Clinical Practice: A Comprehensive Review and Database Update

Area of Science:

• Genetics and Molecular Biology
• Oncology
• Developmental Biology

Background:

• The RET gene encodes a receptor tyrosine kinase crucial for development and physiology.
• Dysregulation of RET signaling is implicated in various human diseases.
• Understanding RET mutations is key to diagnosing and treating associated disorders.

Purpose of the Study:

• To provide a comprehensive review of RET-associated disorders.
• To elucidate molecular mechanisms of RET activation and clinical phenotypes.
• To present an updated database of RET mutations for diagnostic and therapeutic insights.

Main Methods:

• Integrated and curated data from Leiden Open Variation Database (LOVD), Cancer Knowledge Base (CKB), and ClinVar.
• Systematic analysis of identified RET mutations and their characteristics.
• Focused on pathogenic variants, their types, and distribution.

Main Results:

• Identified 78 pathogenic RET mutations, predominantly missense variants (91.0%).
• Observed significant mutation clustering in exons 10-11 (~60% of cases).
• Highlighted exons 10-11 as potential mutational hotspots with functional relevance.

Conclusions:

• Aberrant RET activation drives diverse diseases including MEN2A, MTC, Hirschsprung disease, and pheochromocytoma.
• Activating missense variants, gene fusions, and overexpression are key mechanisms.
• A curated RET mutation database is vital for molecular diagnostics and personalized medicine.