Molecular profiling of gastric neuroendocrine carcinomas.

451 Background: Reports of comprehensive genetic analysis of gastric neuroendocrine carcinoma (G-NEC) are limited, and few have described the tumorigenesis of G-NEC. G-NEC usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because these two tumors share common pathogenic mutations and loss of heterozygosity. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis than that of G-NEC with adenocarcinoma. This study aimed to elucidate the tumorigenesis of G-NEC by focusing on the percentage of NEC component, using comprehensive genetic analysis. Methods: Of the 698 patients who had undergone gastrectomy for gastric cancer between January 2014 and March 2019, this study included 13 patients with G-NEC. Comprehensive genetic analysis using whole-exome sequencing, deep sequencing using a target gene panel, and microarray analysis were performed. NEC was classified according to the 2010 WHO classification. G-NEC without an adenocarcinoma component was defined as pure NEC. Results: There were six patients with mixed adeno-neuroendocrine carcinoma (MANEC), four patients with NEC, and three patients with pure NEC. TP53 was detected as the most frequent gene mutation, independent of classification (85%). RB1, ANKRD17, KMT2C, LTBP1, MAATS1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Gene expression analysis showed that six key transcripts of importance in NEC tumorigenesis were upregulated in two patients with pure NEC, while they were downregulated in all six MANEC patients. Conclusions: NEC and MANEC with adenocarcinoma components tend to share common pathogenic mutations, but Pure NEC has different genomic and transcriptomic characteristics than other NECs. This suggests that pure NEC has a different mechanism of tumorigenesis than other G-NECs with adenocarcinoma. This is the first study to present a comprehensive genetic analysis of G-NEC, classified by the percentage of NEC components.