Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression (Cancer Cell, Oct 2023)

Kie Kyon Huang¹, Haoran Ma¹, Roxanne Hui Heng Chong², Tomoyuki Uchihara¹, Benedict Shi Xiang Lian¹, Feng Zhu², Taotao Sheng³, Supriya Srivastava², Su Ting Tay¹, Raghav Sundar⁴, Angie Lay Keng Tan¹, Xuewen Ong¹, Minghui Lee¹, Shamaine Wei Ting Ho³, Tom Lesluyes⁵, Hassan Ashktorab⁶, Duane Smoot⁷, Peter Van Loo⁸, Joy Shijia Chua², Kalpana Ramnarayanan¹, Louis Ho Shing Lau⁹, Takuji Gotoda¹⁰, Hyun Soo Kim¹¹, Tiing Leong Ang¹², Christopher Khor¹³, Jonathan Wei Jie Lee¹⁴, Stephen Kin Kwok Tsao¹⁵, Wei Lyn Yang¹⁵, Ming Teh¹⁶, Hyunsoo Chung¹⁷, Jimmy Bok Yan So¹⁸, Khay Guan Yeoh¹⁹, Patrick Tan²⁰; Singapore Gastric Cancer Consortium

Affiliations

¹Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
²Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
³Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
⁴Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Haematology-Oncology, National University Health System, Singapore 119074, Singapore.
⁵The Francis Crick Institute, London, UK.
⁶Department of Medicine, Howard University, Washington, DC, USA.
⁷Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA.
⁸The Francis Crick Institute, London, UK; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
¹⁰Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
¹¹Department of Internal Medicine, Yonsei University Wonju College of Medicine, Seoul, Korea.
¹²Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore 529889, Singapore.
¹³Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore 169854, Singapore.
¹⁴Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; iHealthtech, National University of Singapore, Singapore, Singapore; SynCTI, National University of Singapore, Singapore 117599, Singapore; Department of Gastroenterology & Hepatology, National University Hospital, Singapore 119074, Singapore.
¹⁵Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore 308433, Singapore.
¹⁶Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
¹⁷Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. Electronic address: h.chung@snu.ac.kr.
¹⁸Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Surgical Oncology, National University Cancer Institute of Singapore (NCIS), Singapore, Singapore. Electronic address: jimmyso@nus.edu.sg.
¹⁹Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Gastroenterology & Hepatology, National University Hospital, Singapore 119074, Singapore. Electronic address: mdcykg@nus.edu.sg.
²⁰Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore; Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore. Electronic address: gmstanp@duke-nus.edu.sg.

Abstract

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.

PMID: 37890493 DOI: 10.1016/j.ccell.2023.10.004

Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression (Cancer Cell, Oct 2023)

Affiliations

Abstract

CSI Web Experience Survey Form

Please Rate Your Satisfaction