RET
Summary
RET is a proto-oncogene encoding a receptor tyrosine kinase for GDNF-family ligands. Germline gain-of-function mutations cause MEN2A, MEN2B, and familial medullary thyroid carcinoma, while loss-of-function mutations/deletions are associated with Hirschsprung disease. RET is also a target for certain tyrosine kinase inhibitors in oncology.
Detail
RET (REarranged during Transfection) encodes a transmembrane receptor tyrosine kinase expressed in neural crest-derived tissues, including thyroid C cells, adrenal medulla, and enteric neurons. It signals through binding of GDNF-family ligands (GDNF, neurturin) with co-receptors (GFRα), activating RAS/MAPK and PI3K/AKT pathways important for cell growth, survival, and differentiation—particularly enteric nervous system development.
Germline activating (gain-of-function) point mutations in RET cause autosomal dominant multiple endocrine neoplasia syndromes: - MEN2A: medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid hyperplasia (codon 634 mutations common) - MEN2B: MTC, pheochromocytoma, mucosal neuromas, marfanoid habitus (codon 918 mutation, M918T) - Familial MTC (FMTC): MTC without other features
Because RET mutations have high penetrance for MTC, prophylactic thyroidectomy is recommended in mutation carriers, with timing based on genotype-phenotype risk stratification (MEN2B highest risk, earliest surgery).
Conversely, loss-of-function mutations or reduced RET expression impair neural crest cell migration to the distal colon, causing aganglionic megacolon (Hirschsprung disease), characterized by absence of enteric ganglia in the rectosigmoid colon, presenting with failure to pass meconium and chronic constipation in neonates.
Somatic RET mutations/rearrangements (e.g., RET/PTC fusions) also occur sporadically in papillary thyroid carcinoma (especially radiation-induced) and some non-small cell lung cancers. Selective RET inhibitors (selpercatinib, pralsetinib) are used to treat RET-altered thyroid and lung cancers.
Key testing: Genetic screening for RET mutations is standard in patients with MTC or pheochromocytoma to identify MEN2 and guide family screening/management.
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- UpToDate: Multiple Endocrine Neoplasia Type 2
- NCBI GeneReviews: RET-Related Disorders
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