Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach.

e16094 Background: Hepatoid adenocarcinoma (HAC) is a rare pathological subtype of extrahepatic tumor, featured by hepatoid differentiation and α-fetoprotein (AFP)-production. Hepatoid adenocarcinoma of the stomach (HAS), accounting for 0.17 to 15% of gastric cancers, is the most common subtype of HAC, and has attracted increasing attention duo to its high degree of malignancy. Compared with classic gastric cancer (GC), HAS showed a higher rate of vascular invasion, lymph node metastasis, and liver metastasis, with only 9% survival at 5 years. In this study, we aim to investigate the molecular features of HAS and identify the potential therapeutic targets for HAS. Methods: We conducted whole-exome sequencing (WES) of 40 paired tumor and normal samples, including 25 HAS, 6 HAC of other organ and 9 AFP-producing gastric cancer (AFPGC). All patients underwent radical surgery at Shanghai Zhongshan Hospital between July 2013 and September 2017. qRT-PCR, Western blot and immunohistochemistry were detected to explore MUC19 expression in HAS. CCK8 assay, Transwell assay, immunofluorescence assay and subcutaneous xenograft tumor model were used to detect functional effects and the mechanism of MUC19. Results: In HAS patients, the top 5 frequently mutated genes were TP53 (44%), TTN (44%), MUC19 (40%), CCNE1 (28%) and CDC27 (28%). Further compared with TCGA datasets, MUC19, CCNE1, CDC27 mutations were almost undetectable in STAD, CRC and HCC. In terms of CNV analysis, VSTM2B, PLEKHF1, POP4, URI1 and TERT were the most frequently amplificated genes in HAS tumor tissues. Interestingly, amplification of 4 genes (VSTM2B, CCNE1, LEKHF1, POP4), which located in chr19q12, was significantly associated with poor prognosis. The tumor mutational burden (TMB) levels and AFP expression of HAS and AFPGC patients were no significantly different, while patients with higher TMB had a remarkably longer overall survival ( p= 0.0065). Moreover, we found MUC19 expression was positively correlated with AFP levels in HAS and MUC19 promoted the transcription of AFP in GC cells. Mechanistically, MUC19 contributed to the aggressive malignancy phenotypes of GC cells through activating the Wnt/β-catenin signaling pathway. Conclusions: MUC19 may be a potential target for HAS diagnosis and treatment. Amplification of genes located in chr19q12 occurred frequently in HAS and were associate with poor prognosis. TMB was sensitive for the overall survival of HAS patients.