Landscape of Phenotype-Genotype Correlations in Romanian Patients with Medullary Thyroid Carcinoma

To comprehensively characterize the genetic landscape of medullary thyroid carcinoma (MTC) in a Romanian cohort.

Germline and somatic RET testing were performed in 164 MTC patients (105 sporadic, 59 hereditary) consecutively enrolled at a single tertiary center (2021-2024) using genomic DNA or DNA extracted from fresh surgical or paraffin-embedded pathology specimens.

Hereditary MTC (hMTC) accounted for 59/164 (35.9%) cases. Among hMTC, 58/59 (98.3%) had MEN2 (72.4% classic, 5.2% with cutaneous lichen amyloidosis, 5.2% with Hirschsprung disease, and 17.2% with familial medullary thyroid carcinoma), and 1/59 (1.7%) had MEN3. Codon 634 mutations were the most prevalent (33/59, 55.9%). Extracellular cysteine-rich domain mutations were significantly more prevalent in syndromic cases (p = 0.006), while non-cysteine mutations were predominant in apparently sporadic cases (p = 0.006). In advanced MTC (stage III/IV or metastatic), the somatic M918T mutation was the most common (15/20, 75% cases).

Germline RET screening is mandatory for all MTC cases. Somatic testing is critical in advanced disease, where M918T prevails in 75% of cases and guides tyrosine kinase inhibitor therapy. Codon 634 is the most frequent mutation in Romanian MTC, highlighting regional variation warranting population-adjusted screening and earlier prophylactic thyroidectomy.