mTOR activation in medullary thyroid carcinoma with RAS mutation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Medullary thyroid carcinoma (MTC) is often driven by Rearranged during transfection (RET) mutations.
• RAS mutations have emerged as a significant genetic event in sporadic MTC, challenging the established RET paradigm.
• Understanding alternative molecular pathways, such as mTOR, is crucial for MTC pathogenesis.

Purpose of the Study:

• To investigate the activation of the mTOR pathway in MTC with RET and RAS mutations.
• To determine the prevalence of RET and RAS mutations in a cohort of MTC patients.
• To explore the correlation between specific mutations and mTOR pathway activation markers.

Main Methods:

• Genotyping of RET, H-RAS, and K-RAS mutations in 87 MTC samples.
• Immunohistochemical analysis of phospho-S6 ribosomal protein (p-S6) and PTEN expression to assess mTOR pathway activation.
• Correlation analysis between mutation status, p-S6, and PTEN expression, and clinicopathological features.

Main Results:

• RET mutations were found in 52.9% of MTC cases, while RAS mutations were present in 12.6% and mutually exclusive with RET.
• RAS mutations were significantly associated with increased p-S6 expression, indicating mTOR pathway activation (P=0.007).
• Elevated p-S6 expression correlated with tumor invasiveness and lymph node metastasis (P=0.042, P=0.046).

Conclusions:

• This study confirms RAS mutations in 14.3% of sporadic MTCs and establishes their association with mTOR pathway activation.
• pS6 expression serves as a potential biomarker for mTOR activation and may indicate invasive MTC.
• These findings highlight the role of the mTOR pathway in MTC progression and suggest therapeutic targets.