Age-related remodelling of oesophageal epithelia by mutated cancer drivers

Akira Yokoyama, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Yasuhito Nannya, Hiromichi Suzuki, Yasuhide Takeuchi, Yusuke Shiozawa, Yusuke Sato, Kosuke Aoki, Soo Ki Kim, Yoichi Fujii, Kenichi Yoshida, Keisuke Kataoka, Masahiro M. Nakagawa, Yoshikage Inoue, Tomonori Hirano, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Yoshitaka Nishikawa, Yusuke Amanuma, Shinya Ohashi, Ikuo Aoyama, Takahiro Horimatsu, Shin’ichi Miyamoto, Shigeru Tsunoda, Yoshiharu Sakai, Maiko Narahara, J. B. Brown, Yoshitaka Sato, Genta Sawada, Koshi Mimori, Sachiko Minamiguchi, Hironori Haga, Hiroshi Seno, Satoru Miyano, Hideki Makishima, Manabu Muto and Seishi Ogawa ()
Additional contact information
Akira Yokoyama: Kyoto University
Nobuyuki Kakiuchi: Kyoto University
Tetsuichi Yoshizato: Kyoto University
Yasuhito Nannya: Kyoto University
Hiromichi Suzuki: Kyoto University
Yasuhide Takeuchi: Kyoto University
Yusuke Shiozawa: Kyoto University
Yusuke Sato: Kyoto University
Kosuke Aoki: Kyoto University
Soo Ki Kim: Kyoto University
Yoichi Fujii: Kyoto University
Kenichi Yoshida: Kyoto University
Keisuke Kataoka: Kyoto University
Masahiro M. Nakagawa: Kyoto University
Yoshikage Inoue: Kyoto University
Tomonori Hirano: Kyoto University
Yuichi Shiraishi: The University of Tokyo
Kenichi Chiba: The University of Tokyo
Hiroko Tanaka: The University of Tokyo
Masashi Sanada: Clinical Research Center, Nagoya Medical Center
Yoshitaka Nishikawa: Kyoto University Hospital
Yusuke Amanuma: Kyoto University Hospital
Shinya Ohashi: Kyoto University Hospital
Ikuo Aoyama: Kyoto University Hospital
Takahiro Horimatsu: Kyoto University Hospital
Shin’ichi Miyamoto: Kyoto University
Shigeru Tsunoda: Kyoto University
Yoshiharu Sakai: Kyoto University
Maiko Narahara: McGill University, Montreal
J. B. Brown: Life Science Informatics Research Unit, Kyoto University
Yoshitaka Sato: Sato Clinic
Genta Sawada: Kyushu University Beppu Hospital
Koshi Mimori: Kyushu University Beppu Hospital
Sachiko Minamiguchi: Kyoto University
Hironori Haga: Kyoto University
Hiroshi Seno: Kyoto University
Satoru Miyano: The University of Tokyo
Hideki Makishima: Kyoto University
Manabu Muto: Kyoto University Hospital
Seishi Ogawa: Kyoto University

Nature, 2019, vol. 565, issue 7739, 312-317

Abstract: Abstract Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which—depending on lifestyle risks—may affect cancer development.

Date: 2019
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DOI: 10.1038/s41586-018-0811-x

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