Abstract 739: Whole-exome sequencing of neuroendocrine neoplasm of the liver reveals recurrent mutations in components of RTK-RAS pathways
Authors: Chen Lingli , Ji Yuan , Zhao Jing , Hao Lingtong , Li Yixue , Zhang Xi , Sun Huichuan , Luo Rongkui , Han Jing , Huang Jie , Hou Yingyong , Liu Jia 
Published: August 2019

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 &lt;0.001). NEC tumors were characterized by the mutation signature associated with failure double-strand DNA break repair homologous recombination on its high mutation burdern in samples harbouring BRCA1 or BRCA2 mutation (6/7 vs. 0/9, p &lt;0.001), neural cell adhesion molecule (NCAM) positive (6/7 vs. 1/9, p &lt;0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., P53-Rb and Wnt), and signatures related to poor clinical outcome. In the NET type, there was a significant correlation in the copy number variation of the ICC, suggesting a clonal origin. Exome sequencing revealed an average of 104 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (4/7, 57.1%) in phNECs. Intratumor expression of PD-L1 was significantly associated with poorly-differentiated NEC, p53-positive patients. Overall survival rate was significantly correlated to tumor differentiation, growth pattern, necrosis, TP53 mutation (P&lt;0.05), but not correlated to PD-L1expression and vascular invasion(P&gt;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.