Clinicopathological and genetic characteristics of gastric neuroendocrine tumour (NET) G3 and comparisons with neuroendocrine carcinoma and NET G2

Aims To characterise the clinicopathological and genetic characteristics of gastric neuroendocrine tumour G3 (gNET G3) and to compare them with those of gastric neuroendocrine carcinoma (gNEC) and gNET G2. Methods and results A total of 115 gastric neuroendocrine neoplasms (NENs) were included, of which gNET G3 was different from gNET G1/G2 in terms of tumour location ( P = 0.029), number ( P = 0.003), size ( P = 0.010), the Ki67 index ( P < 0.001), lymph node metastasis ( P < 0.001) and TNM stage ( P = 0.011), and different from gNEC/gastric mixed neuroendocrine–non‐neuroendocrine neoplasm (gMiNEN) in terms of tumour size ( P = 0.010) and the Ki67 index ( P = 0.001). High‐resolution copy number (CN) profiling and validation experiments showed CN gains and high expression of DLL3 in gNET G3. Hierarchical clustering analysis based on CN characteristics showed that gNET G3 was separated from gNEC but mixed with gNET G2. In gene set enrichment analysis, eight pathways were significantly enriched in gNEC when comparing gNET G3 and gNEC ( P < 0.05), while no pathways were enriched when comparing gNET G3 and gNET G2. Whole‐exome sequencing and validation experiments showed nonsense mutation of TP53 in one gNET G3, with wild‐type staining for p53. In gNEC, TP53 mutations were detected in four of eight cases, and abnormal expression of p53 was detected in all cases. Conclusion Gastric NET G3 is a distinct entity with unique genetic characteristics, which are different from those of gNEC than gNET G2. Our results provide insight into some molecular alterations that may contribute to the development and progression of gNET G3 and serve as potential therapeutic targets.