Germline Mutation Landscape of Neuroendocrine Tumors in the Chinese Population.

Certain hereditary syndromes increase the incidence of neuroendocrine tumors (NETs), suggesting germline variation may play a role in NET pathogenesis. However, the germline mutation spectrum in Chinese NET patients remains unclear. This study aimed to investigate the germline genetic variations and associated clinicopathological features in Chinese NET patients. A single-center retrospective study was conducted at the Cancer Hospital of Chinese Academy of Medical Sciences; 453 histologically confirmed NET patients who received germline genetic testing between June 2018 and March 2025 were enrolled. Germline DNA extracted from saliva or blood samples was analyzed using multigene panels and whole-exome sequencing. Results showed 11.5% (52/453) cases carried germline pathogenic or likely pathogenic variants (P/LPVs) across 28 cancer predisposing genes. MEN1 was the most frequently mutated gene, accounting for 3.5% (16/453) of all enrolled patients, followed by PALB2, SDHB, and BRIP1. The most common variant of uncertain significance (VUS) was found in MUTYH. Compared with non-carriers, P/LPV carriers were characterized by a significantly younger age at diagnosis (p < 0.001), male predominance (p = 0.008), higher tumor grade (p = 0.006), a stronger family history of cancer (p = 0.047), different primary tumor locations (p < 0.001), lower somatostatin receptor 2 expression (p = 0.010), and more aggressive tumor behavior, including higher metastatic rate (p = 0.002) and advanced stage (p = 0.011). Furthermore, patients with MEN1 P/LPVs had more mediastinal tumors and a younger age than those with non-MEN1 P/LPVs. This study, which is the largest to date regarding germline variations in Chinese patients with NETs, reveals a distinct mutational profile and identifies the unique clinicopathological features among carriers of germline P/LPVs.