{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan",
        "Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan",
        "Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Ya-Hsuan Chang"
    },
    {
      "affiliations": [
        "Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan",
        "Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan",
        "Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan"
      ],
      "name": "Tzu-Chan Hong"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Kuen-Tyng Lin"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Yi-Jing Hsiao"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Hsiang-En Hsu"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Juanilita T. Waniwan"
    },
    {
      "affiliations": [
        "Ph.D. Program in Bioinformatics, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan",
        "Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan"
      ],
      "name": "Rodrigo Espinoza Silva"
    },
    {
      "affiliations": [
        "Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan",
        "Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "I-Rue Lai"
    },
    {
      "affiliations": [
        "Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan"
      ],
      "name": "Po-Chu Lee"
    },
    {
      "affiliations": [
        "Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan"
      ],
      "name": "Ming-Tsan Lin"
    },
    {
      "affiliations": [
        "Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan",
        "Department of Pathology, Good Liver Clinic, Taipei, Taiwan"
      ],
      "name": "Chia-Tung Shun"
    },
    {
      "affiliations": [
        "Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan",
        "Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan"
      ],
      "name": "Min-Shu Hsieh"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan",
        "Department of Biological Science and Technology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, Hsinchu, Taiwan"
      ],
      "name": "Yi-Ju Chen"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan"
      ],
      "name": "Song-Wei Wang"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan",
        "Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Wen-Hung Hsu"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan",
        "Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "I-Chen Wu"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan",
        "Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Yao-Kuang Wang"
    },
    {
      "affiliations": [
        "Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Ching-Chun Li"
    },
    {
      "affiliations": [
        "Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan",
        "Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan",
        "Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Jaw-Yuan Wang"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Yin-Chen Hsu"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Hao Fang"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Ze-Shiang Lin"
    },
    {
      "affiliations": [
        "Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan"
      ],
      "name": "Wen-Hsin Chang"
    },
    {
      "affiliations": [
        "Institute of Statistical Science, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Jyun-Hong Lin"
    },
    {
      "affiliations": [
        "Institute of Statistical Science, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Yan-Si Chen"
    },
    {
      "affiliations": [
        "Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan"
      ],
      "name": "Ying-Chieh Ko"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Chi-Ya Shen"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Yan-Ming Chen"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Chia-Yu Wang"
    },
    {
      "affiliations": [
        "Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Yu-Teng Jheng"
    },
    {
      "affiliations": [
        "Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Wen-Yi Liu"
    },
    {
      "affiliations": [
        "National Center for High-performance Computing, National Institutes of Applied Research, Hsinchu, Taiwan"
      ],
      "name": "Yu-Tai Wang"
    },
    {
      "affiliations": [
        "National Center for High-performance Computing, National Institutes of Applied Research, Hsinchu, Taiwan"
      ],
      "name": "Chang-Wei Yeh"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan"
      ],
      "name": "Pei-Rong Huang"
    },
    {
      "affiliations": [
        "Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan",
        "Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan"
      ],
      "name": "Jyh-Ming Liou"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan",
        "National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan"
      ],
      "name": "Li-Tzong Chen"
    },
    {
      "affiliations": [
        "Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan"
      ],
      "name": "Chia-Li Han"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan",
        "Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Deng-Chyang Wu"
    },
    {
      "affiliations": [
        "Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan",
        "Institute of Statistical Science, Academia Sinica, Taipei, Taiwan",
        "Ph.D. Program in Microbial Genomics, National Chung Hsing University, Taichung, Taiwan"
      ],
      "name": "Hsuan-Yu Chen"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Sung-Liang Yu"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan"
      ],
      "name": "Ming-Shiang Wu"
    },
    {
      "affiliations": [
        "Institute of Chemistry, Academia Sinica, Taipei, Taiwan",
        "Department of Chemistry, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Yu-Ju Chen"
    },
    {
      "affiliations": [],
      "name": "Taiwan Cancer Moonshot Program"
    }
  ],
  "title": "Integrative proteogenomics maps multifactorial aetiology, progression and therapeutic vulnerabilities in gastric cancer",
  "uid": "71da9eef-fe8c-5399-b0b0-2157a337d4c3"
}