117P - Methylome and transcriptome profiling of hepatoid adenocarcinoma of the stomach

Background

Hepatoid adenocarcinoma of stomach (HAS) is a rare subtype of gastric cancer (GC) with hepatocyte-like differentiation and a dismal prognosis. Although HAS has different histological and molecular properties and more aggressive biological behavior, most patients with HAS still receive the same regimen as usual GC. A comprehensive understanding of the molecular properties of HAS may provide insights into personalized diagnosis and treatment, however, this area is under-studied.

Methods

We aimed to explore methylome and transcriptome profiling of HAS in a relatively precise scenario. The laser capture microdissection (LCM) was used to isolate thirty-two formalin fixed paraffin-embedded (FFPE) tissue into gastric adenocarcinoma section (GAC) and hepatocellular-like section (HAS). According to the manufacturer's protocol, DNA-associated methylation sequencing and RNA-associated transcriptome sequencing were performed.

Results

With Laser-Capture Microdissection (LCM) technique, we separate HAS FFPE sample into gastric adenocarcinoma component (GAC) and HAS component. The whole genome RNAseq and methylation sequencing (GMseq) were used to explore HAS expression patterns and methylation modification profile. We found that differentially methylated cytosine was effective in distinguishing GAC from HAS, and stem cell-related gene expression and pathway enrichment were higher in GAC than in HAS. Correspondingly, HAS showed TNFSF15 gene significantly hypermethylation and lower expression features. In addition, in vivo xenograft models derived from TNFSF15 knockout cells showed higher aggressiveness and hepatocyte-like gene expression. Our study sheds light on the critical role of TNFSF15 in HAS transdifferentiation, and intervening methylation of TNFSF15 may be a clinical option to improve prognosis and reduce metastasis.

Conclusions

In summary, we found that the GAC component has the expression features of pluripotent stem cells and mesothelial cells, and the HAS component has the features of hepatoblast and mature hepatocytes. We propose that GAC mesoderm and endoderm dedifferentiation bias TME as the key role to HAS transdifferentiation and TNFSF15 may be a key regulatory factor in this process.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.