SAT-072 - MEN2A with RET C609Y: Low Biochemical Activity with Favorable Metastatic Profile-Single-Center Experience (1990-2024)

Background:
While codon 634 mutations in the RET gene are well-characterized in MEN2A, the clinical significance of the less common C609Y mutation remains underexplored. Understanding the prevalence and clinical implications of RET mutations in patients with MEN2A can enhance risk stratification and management strategies. This study aims to retrospectively identify patients with MEN2A, evaluate associated risk factors and outcomes, and understand genotype-phenotype correlations.

Methods:
We retrospectively reviewed pathology reports of patients who underwent adrenalectomy for pheochromocytoma or thyroidectomy for MTC at the University of Missouri from 1990 to 2024. Data included demographics, RET genetic testing, clinical presentation, and outcomes. Data were then analyzed for risk factors and survival.

Results:
Thirty-eight MEN2A patients were identified, with a median follow-up of 144 months. The cohort consisted of 61% females and 39% males, with a mean age at diagnosis of 41 years. Neck swelling was the most common initial presentation among index patients (18.4%). MTC was present in 97.5% of patients; pheochromocytoma and hyperparathyroidism occurred in 17.5% and 15%, respectively. RET mutation data were available in 85% of cases, with C609Y being the predominant mutation (total 68.6% [45.8% in index cases vs 54.2% in relatives; p=0.63]). Metastasis was absent in 67.6%; when present, neck lymph nodes were most common (10.8%). Metastasis correlated with older age (p=0.024), elevated calcitonin (p=0.0004), and CEA (p=0.020). The C609Y mutation was associated with lower metastasis rates (p=0.003) and lower calcitonin levels (p=0.007). Patients without C609Y had higher urine metanephrines (mean 2458.2 ug/24h), suggesting a more prominent endocrine activity. Biochemical cure post-thyroidectomy was achieved in 60.6%. At the last follow-up, 94.74% of patients (n=36) were alive; among the two deaths, one was due to sepsis and the other was of unknown cause.
Notably, index cases were diagnosed approximately 15 years later than relatives (mean age 48.8 vs 34.1 years). Index cases also exhibited markedly higher calcitonin and urine catecholamines/metanephrines at diagnosis (mean calcitonin 451.3 vs 360.5 pg/mL; urine metanephrines 2,319.4 vs 324.3 µg/24h), reflecting more advanced disease at presentation.

Conclusion:
The C609Y RET mutation, though less common than codon 634, was predominant in our cohort and associated with lower metastatic risk and biochemical activity, suggesting a less aggressive MEN2A phenotype. These findings support C609Y as a distinct clinical subset, warranting further study for prognostic and therapeutic guidance. Our results also highlight the importance of broad genetic testing for at-risk individuals, regardless of family history. The observed earlier diagnosis in relatives reinforces the value of early screening and intervention.

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