Integrative proteogenomics maps multifactorial aetiology, progression and therapeutic vulnerabilities in gastric cancer
Journal
Gut
Journal Volume
75
Journal Issue
5
Start Page
886
End Page
904
ISSN
0017-5749
1468-3288
Date Issued
2026-01-30
Author(s)
Chang, Ya-Hsuan
Lin, Kuen-Tyng
Hsiao, Yi-Jing
Hsu, Hsiang-En
Waniwan, Juanilita T.
Silva, Rodrigo Espinoza
Lai, I-Rue
Chen, Yi-Ju
Wang, Song-Wei
Hsu, Wen-Hung
Wu, I-Chen
Wang, Yao-Kuang
Li, Ching-Chun
Wang, Jaw-Yuan
Hsu, Yin-Chen
Fang, Hao
Lin, Ze-Shiang
Chang, Wen-Hsin
Lin, Jyun-Hong
Chen, Yan-Si
Ko, Ying-Chieh
Shen, Chi-Ya
Chen, Yan-Ming
Wang, Chia-Yu
Jheng, Yu-Teng
Liu, Wen-Yi
Wang, Yu-Tai
Yeh, Chang-Wei
Huang, Pei-Rong
Chen, Li-Tzong
Han, Chia-Li
Wu, Deng-Chyang
Chen, Hsuan-Yu
Chen, Yu-Ju
et al.
Abstract
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. Among HP-negative tumours, a Streptococcus-enriched subtype associated with tight-junction (CLDN18.2/ZO-1/OCLN) disruption and epithelial-mesenchymal transition, whereas a subset of clinically aggressive cases retained CLDN18.2-high epithelial-stable subtype for therapeutic accessibility. An independent cohort revealed gastric juice-derived Streptococcus anginosus abundance inversely correlated with tight-junction proteins. Anatomical mapping reveals location-specific, sex-specific, subtype-specific oncogenic networks and kinase activity, including CDK4 activation in clinical biomarker-negative tumours. Decision-tree models combining exposure and proteome-immune states refined recurrence and survival prediction beyond stage.
Conclusion: This proteogenomic framework defines exposure-informed and microbiome-informed gastric cancer subtypes, providing a molecular schema for patient stratification, prevention and actionable therapeutic vulnerabilities.
Subjects
GASTRIC CANCER
MICROBIOME
MOLECULAR CARCINOGENESIS
MOLECULAR GENETICS
PROTEOMICS
Publisher
BMJ
Type
journal article