Background and Aim:
Gastric cancer, ranking as the fifth most prevalent cancer globally, involves complex etiologies, including but not limited to H. pylori infection. This interim report is part of a comprehensive multi-omic analysis from the Taiwan Cancer Moonshot Project on Gastric Cancer. We focuse on using in-depth proteomic workflow and genomic analysis to unveil distinct molecular pathways in gastric cancer, particularly considering the H. pylori infection status.

Methods:
In this large-scale, multi-omic study encompassing genetic, mRNA expression, proteomic, and phosphoproteomic data, we prospectively collect paired gastric cancer and adjacent non-cancer surgical specimens from tertiary referral centers in Taiwan. In the ongoing recruitment targeting more than 200 cases, we will present the multi-omic findings from about 100 cases in this interim analysis, of which the comprehensive proteomic data from 75 samples are discussed first in this abstract. We highlight an in-depth proteomic and phosphoproteomic evaluation, with the identified proteins over 11000, by employing a TMT 11-plex-based workflow. Through Principal Component Analysis (PCA) and unsupervised hierarchical clustering, we categorized patients into distinct molecular subtypes.

Results:
From our preliminary cohort subset, the patients were predominantly male (61%), with an average age of 64.25 years (SD 11.25). A significant portion (60%) of patients showed H. pylori association. Post-operative staging indicated early cancer in 21% of cases, with the remainder (79%) requiring chemotherapy. Proteomic analysis delineated five distinct subtypes (P1-P5) with unique clinical characteristics. Subtype P5 was predominantly non-smoking females, while P4 showed a strong correlation with H. Pylori infection (92%). Intriguingly, subtypes P2 and P3 were mostly younger males (80%), with lower H. pylori association (50%). These two subtypes exhibited a high incidence of lymphovascular invasion (81%). Pathway enrichment analysis highlighted a significant role in cellular metabolism regulation for P2 and P3 including oxidative phosphorylation, TCA cycle, and tRNA biosynthesis. Specifically, P3 correlated with aberrant ECM function, and activation of the PI3K-AKT pathway. Notably, immune receptor signaling pathways including BCR, Fc gamma R-mediated phagocytosis, NF-kappa B signaling and EBV infection related pathway were more prevalent in non-H. pylori-associated gastric cancers, while H. pylori-positive cases showed enhanced autophagy pathways.

Conclusion:
This interim report from the Taiwan Cancer Moonshot Project on Gastric Cancer offers pioneering insights into the proteomic diversity of gastric cancer, with a novel emphasis on H. pylori infection status. By shedding light on unique therapeutic pathways, this research paves the way for innovative and personalized treatment approaches.

Figure 1. Graphical Overview of Clinical and Pathological Characteristics in the Gastric Cancer Cohort.

Figure 2. Hierarchical Clustering and Relative Expression Profiling in Proteomic Analysis of Gastric Cancer

Yu-Ju Chen

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