TY - JOUR
T1 - Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression
AU - Singapore Gastric Cancer Consortium
AU - Huang, Kie Kyon
AU - Ma, Haoran
AU - Chong, Roxanne Hui Heng
AU - Uchihara, Tomoyuki
AU - Lian, Benedict Shi Xiang
AU - Zhu, Feng
AU - Sheng, Taotao
AU - Srivastava, Supriya
AU - Tay, Su Ting
AU - Sundar, Raghav
AU - Tan, Angie Lay Keng
AU - Ong, Xuewen
AU - Lee, Minghui
AU - Ho, Shamaine Wei Ting
AU - Lesluyes, Tom
AU - Ashktorab, Hassan
AU - Smoot, Duane
AU - Van Loo, Peter
AU - Chua, Joy Shijia
AU - Ramnarayanan, Kalpana
AU - Lau, Louis Ho Shing
AU - Gotoda, Takuji
AU - Kim, Hyun Soo
AU - Ang, Tiing Leong
AU - Khor, Christopher
AU - Lee, Jonathan Wei Jie
AU - Tsao, Stephen Kin Kwok
AU - Yang, Wei Lyn
AU - Teh, Ming
AU - Chung, Hyunsoo
AU - So, Jimmy Bok Yan
AU - Yeoh, Khay Guan
AU - Tan, Patrick
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/12/11
Y1 - 2023/12/11
N2 - 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.
AB - 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.
KW - cancer screening
KW - cell-of-origin
KW - gastric cancer
KW - intestinal metaplasia
KW - pre-cancer
KW - single-cell sequencing
KW - spatial transcriptomics
KW - targeted DNA sequencing
KW - transcriptome sequencing
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U2 - 10.1016/j.ccell.2023.10.004
DO - 10.1016/j.ccell.2023.10.004
M3 - Article
C2 - 37890493
AN - SCOPUS:85179119520
SN - 1535-6108
VL - 41
SP - 2019-2037.e8
JO - Cancer cell
JF - Cancer cell
IS - 12
ER -