Integrative proteogenomics maps multifactorial aetiology, progression and therapeutic vulnerabilities in gastric cancer

Background Gastric cancer, with disproportionately higher incidence in East Asia, arises from complex host - microbiome - environment interactions beyond Helicobacter pylori (HP) infection. However, the molecular architecture linking environmental carcinogens, microbial succession and host response remains unclear.

Objective To delineate multifactorial aetiologies and clinically actionable subtypes/biomarkers of gastric cancer through integrative proteogenomic, microbial and environmental exposure profiling. Design We established a multiomics atlas of paired tumour, adjacent mucosa tissues and blood from 154 treatment-naïve Taiwanese patients, integrating whole-exome sequencing, RNA-seq, proteome and phosphoproteome profiling with carcinogen signatures, HP status, microbiome composition and refined anatomical mapping.

Cell-based functional assays tested carcinogen effects. Microbial subtype was assessed in an independent cohort.

Results A polycyclic-aromatic-hydrocarbon signature, dibenz[a,h]acridine, emerged as a high-risk exposure promoting invasion, immune suppression and poor survival, significantly exceeding nitrosamine-linked risk in this cohort. Multilayer integration defined three initiation ecologies: HP-driven inflammatory, non-HP microbiome-enriched immune-silent and HP-free microbially depleted states.