Integrative proteogenomics maps multifactorial aetiology, progression and therapeutic vulnerabilities in gastric cancer.
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Chang Ya-Hsuan, Hong Tzu-Chan, Lin Kuen-Tyng, Hsiao Yi-Jing, Hsu Hsiang-En, Waniwan Juanilita T, Silva Rodrigo Espinoza, Lai I-Rue, Lee Po-Chu, Lin Ming-Tsan, Shun Chia-Tung, Hsieh Min-Shu, 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, Liou Jyh-Ming, Chen Li-Tzong, Han Chia-Li, Wu Deng-Chyang, Chen Hsuan-Yu, Yu Sung-Liang, Wu Ming-Shiang, Chen Yu-Ju, Taiwan Cancer Moonshot Program
Аннотация
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.