정현수 (서울대학교 의과대학) | 한빛사논문 > 한빛사

한빛사논문

조회766

서울대학교 의과대학

Cancer Cell, Oct 20 2023, S1535-6108(23)00360-4 | https://doi.org/10.1016/j.ccell.2023.10.004 Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

Kie Kyon Huang ^1,28, Haoran Ma ^1,28, Roxanne Hui Heng Chong^2,28, Tomoyuki Uchihara ¹, Benedict Shi Xiang Lian ¹, Feng Zhu ², Taotao Sheng ³, Supriya Srivastava ², Su Ting Tay¹, Raghav Sundar ^1,2,4, Angie Lay Keng Tan ¹, Xuewen Ong ¹, Minghui Lee ¹, Shamaine Wei Ting Ho ³, Tom Lesluyes⁵, Hassan Ashktorab ⁶, Duane Smoot⁷, Peter Van Loo ^5,8,9, Joy Shijia Chua ², Kalpana Ramnarayanan ¹, Louis Ho Shing Lau ¹⁰, Takuji Gotoda ¹¹, Hyun Soo Kim ¹², Tiing Leong Ang ¹³, Christopher Khor ¹⁴, Jonathan Wei Jie Lee ^2,15,16,23, Stephen Kin Kwok Tsao ¹⁷, Wei Lyn Yang ¹⁷, Ming Teh ¹⁸, Hyunsoo Chung ¹⁹, Jimmy Bok Yan So ^20,21,22, Khay Guan Yeoh ^2,23, Patrick Tan ^{1,3,24,25,26,27,29}, Singapore Gastric Cancer Consortium

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

⁴Department 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

⁸Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

⁹Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

¹⁰Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong

¹¹Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

¹²Department of Internal Medicine, Yonsei University Wonju College of Medicine, Seoul, Korea

¹³Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore 529889, Singapore

¹⁴Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore 169854, Singapore

¹⁵iHealthtech, National University of Singapore, Singapore, Singapore

¹⁶SynCTI, National University of Singapore, Singapore 117599, Singapore

¹⁷Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore 308433, Singapore

¹⁸Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore

¹⁹Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

²⁰Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore

²¹NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

²²Division of Surgical Oncology, National University Cancer Institute of Singapore (NCIS), Singapore, Singapore

²³Department of Gastroenterology & Hepatology, National University Hospital, Singapore 119074, Singapore

²⁴Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore

²⁵Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore

²⁶Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore

²⁷Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore

²⁸These authors contributed equally

²⁹Lead contact

Corresponding authors: Hyunsoo Chung, Jimmy Bok Yan So, Khay Guan Yeoh, Patrick Tan

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.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-30)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

댓글 작성 로그인

CV 열람하기

연락처 보기