Abstract 4747: Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma

Abstract

Abstract AFP-producing gastrointestinal adenocarcinoma (APA-GI) is a rare type of cancer, typically with hepatoid differentiation, chemotherapy resistance and poor prognosis. As the mechanisms of its AFP production and hepatoid differentiation remain unclear, the present study aims to reveal the pathogenesis of APA-GI through genomic and transcriptomic profile analysis. We firstly performed 200 × whole exome sequencing of 29 APA-GI and 8 non-APA-GI cases from our hospital, but found no significant difference in single nucleotide variants (SNV) or insertion/deletion(indels). Additionally, there was no overlap gene when compared with the known genes harbored at 20q11.21-13.12 reported in gastric hepatoid adenocarcinoma. We then performed single-cell mRNA sequencing in one APA-GI, and observed several hepatoid differentiation markers in AFP positive cells including HNF4A and HNF1A. To further determine the specific alterations of APA-GI, we divided 339 gastric cancer patients from TCGA database into AFP-low group and AFP-high group by the level of AFP transcription through a dynamic grouping method named grid search. We performed a series differentially expressed genes detections within different grouping strategies and no significant SNV or indels difference was recognized. We identified hepatoid differentiation markers (i.e. HNF4A, HNF1A and ALB, et al) in AFP-high patients in mRNA level. As the difference of hepatoid differentiation markers only occurred in the mRNA level without DNA alteration, we hypothesized that it was probably caused by epigenetic regulation. We further compared these genes with an epigenetic regulators database named EpiFactors. Finally, it showed CCCTC-Binding Factor Like (CTCFL) was stably related with AFP producing within the grid search. In conclusion, comprehensive genomic analysis of APA-GI shows significant hepatoid differentiation at the transcriptomic level without disease-specific DNA alteration. The pathogenesis of APA-GI may be associated with other mechanisms like epigenetic regulation. Further study was needed to confirm the role of epigenetic regulators we detected in the present study in the development of APA-GI. Citation Format: Jun Li, Xinlin Li, Qiancheng Ye, Yu Tian, Xiangxing Kong, Yue Liu, Xiaoming Xu, Lina Zhang, Qian Xiao, Yeting Hu, Rongzhen Xu, Jingsong Li. Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4747.