PI3K/AKT/mTOR Activation is Associated with Malignant Severity and Poorer Prognosis in Parathyroid Carcinomas.

Context And Objective: Parathyroid carcinoma (PCa) is a rare endocrine neoplasm known for its high recurrence. The specific molecular properties influencing the prognosis of PCa remain largely elusive. The present study was designed to explore the significance of PI3K/AKT/mTOR activation in PCa.

Methods: Over a 10-year period, 64 PCa patients were recruited from dual centers. We analyzed mTORC1 activity in 64 PCa patients and 29 controls, comprising atypical parathyroid tumor (APT), parathyroid adenoma (PAd) and normal parathyroid (PaN) tissues. A panel of selected genes targeting the PI3K/AKT/mTOR pathway (PIK3CA, PTEN, MTOR, TSC1, and TSC2) and CDC73 was performed in 66 available tumor tissues from 64 patients with PCa. Follow-up lasted up to 117 months.

Results: There was intertumoral heterogeneity in mTORC1 activity in parathyroid tumors. Notably, we observed significantly elevated mTORC1 activity in PCa patients compared with controls, as assessed by immunohistochemical staining of tissue sections. Further analysis showed that 48.5% of PCa tumors were classified as 'High mTORC1' (above the predefined threshold), while only 22.7% of tumors in the PAd/APT group met this criterion. Additionally, we detected PI3K/AKT/mTOR variants in 16/66 (24.2%) PCa samples, with the majority lacking CDC73 variants. Higher mTORC1 activity was noted in PCa with PI3K/AKT/mTOR variants than in those without. Compared with those without any targeted variants, the PI3K/AKT/mTOR-mut group presented higher levels of serum PTH, ALP and creatinine, and was associated with significantly lower disease-free survival (DFS) and overall survival (OS) (DFS, p < 0.001; OS, p < 0.01).

Conclusion: Our findings highlight that the activation of the PI3K/AKT/mTOR pathyway in PCa patients suggests their degree of malignancy, possibly leading to poor outcomes.