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

## TL;DR

This study characterizes RET mutations in Romanian patients with medullary thyroid carcinoma, revealing insights into genetic patterns and implications for targeted therapy.

## Contribution

The study provides the first detailed analysis of RET mutations in Romanian MTC patients, emphasizing regional genetic variation and clinical implications.

## Key findings

- Codon 634 mutations were the most prevalent in hereditary MTC cases.
- The somatic M918T mutation was most common in advanced MTC, affecting 75% of cases.
- Extracellular cysteine-rich domain mutations were more frequent in syndromic cases compared to sporadic cases.

## Abstract

The aim of the research was to characterize RET mutations in patients with medullary thyroid carcinoma (MTC) in Romania, considering their relevance for tyrosine kinase inhibitor therapy. Up until this study, due to recent restrictions, no other center in Romania had specifically tested for somatic RET mutations to enable access to targeted therapy. This study included both somatic and germline testing for RET mutations, providing novel insights into the mutational landscape of the Romanian population.

Background/Objective: To comprehensively characterize the genetic landscape of medullary thyroid carcinoma (MTC) in a Romanian cohort. Methods: 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. Results: 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). Conclusions: 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.