Abstract 739: Whole-exome sequencing of neuroendocrine neoplasm of the liver reveals recurrent mutations in components of RTK-RAS pathways

Aims: Primary hepatic neuroendocrine neoplasms (phNENs) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy. Methods: Twenty-one cases of phNENs were graded into stepwise increasing malignant potential groups: neuroendocrine tumor grade 1 (NET G1, 3 cases), grade 2 (NET G2, 9 cases), neuroendocrine carcinoma (NEC, 9 cases) based on mitotic activity and proliferative index, according to WHO Classification of Tumors of the Digestive System (2010). The expression of PD-L1(clone 28-8), p53(DO7), NCAM, RB, and synaptophysin were detected. Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 16 patients with phNENs (9 NETs, 7 NECs) were performed. Comparative genomic analysis was carried out, using independent datasets of pancreas NET (n = 64) and intrahepatic cholangiocarcinoma (ICC) (n = 49). Results: Integrative genomic analysis of phNENs revealed that NEC represents a distinct biliary- derived entity compared with the NET types. NET were, chromosomally stable (mean chromosomal aberrations 4.7 vs. 14.1, p = 0.008), showed significant upregulation of MAPK and PI3K signaling and enrichment of inflammation-related and immune response signatures (p 0.05). Conclusions: phNEN represents a heterogeneous group of tumors, with the NEC type characterized by features of poor prognosis, and the NET type with common lineage for iCCA. PhNET stands alone as a distinct biliary-derived entity associated with chromosomal stability and active RTK-RAS signaling. The elevated expression of immune related genes and pathways in NENs suggests a therapeutic opportunity for immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Lingli Chen, Yuan Ji, Jing Zhao, Lingtong Hao, Yixue Li, Xi Zhang, Huichuan Sun, Rongkui Luo, Jing Han, Jie Huang, Yingyong Hou, Jia Liu. Whole-exome sequencing of neuroendocrine neoplasm of the liver reveals recurrent mutations in components of RTK-RAS pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 739.