Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

• Published in: Cancer cell Vol. 41; no. 12; pp. 2019 - 2037.e8
• Main Authors: Huang, Kie Kyon, Ma, Haoran, Chong, Roxanne Hui Heng, Uchihara, Tomoyuki, Lian, Benedict Shi Xiang, Zhu, Feng, Sheng, Taotao, Srivastava, Supriya, Tay, Su Ting, Sundar, Raghav, Tan, Angie Lay Keng, Ong, Xuewen, Lee, Minghui, Ho, Shamaine Wei Ting, Lesluyes, Tom, Ashktorab, Hassan, Smoot, Duane, Van Loo, Peter, Chua, Joy Shijia, Ramnarayanan, Kalpana, Lau, Louis Ho Shing, Gotoda, Takuji, Kim, Hyun Soo, Ang, Tiing Leong, Khor, Christopher, Lee, Jonathan Wei Jie, Tsao, Stephen Kin Kwok, Yang, Wei Lyn, Teh, Ming, Chung, Hyunsoo, So, Jimmy Bok Yan, Yeoh, Khay Guan, Tan, Patrick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2023; Cell Press
• Subjects: cancer screening; cell-of-origin; gastric cancer; Gastric Mucosa - pathology; Genomics; Humans; intestinal metaplasia; Metaplasia - genetics; pre-cancer; Precancerous Conditions - genetics; Prospective Studies; single-cell sequencing; spatial transcriptomics; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; targeted DNA sequencing; transcriptome sequencing; targeted DNA sequencing; single-cell sequencing; cancer screening; gastric cancer; transcriptome sequencing; intestinal metaplasia; spatial transcriptomics; cell-of-origin; pre-cancer
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.10.004

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception. [Display omitted] •Genomic profiling reveals 26 intestinal metaplasia (IM) driver genes including SOX9•IM lineage heterogeneity harbors a stem-cell subpopulation linked to malignancy•IM molecular subtypes are associated with inflammation and microbial communities•Genomic-clinical models improve identification of IMs at risk of GC progression Intestinal metaplasia (IM) is a pre-malignant condition linked to gastric cancer (GC). Huang et al. analyze a large prospective IM cohort, identifying driver genes, stem cell populations linked to GC, and molecular subtypes associated with inflammation and oral microbes. These results facilitate the use of genomics in GC precision prevention.