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 & 20 others Yoshitaka Nishikawa, Yusuke Amanuma, Shinya Ohashi, Ikuo Aoyama, Takahiro Horimatsu, Shinichi 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, Seishi Ogawa

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)312-317
Number of pages6
JournalNature
Volume565
Issue number7739
DOIs
Publication statusPublished - Jan 17 2019

Fingerprint

Epithelium
Mutation
Clone Cells
Neoplasms
Smoking
Chronology
Esophageal Neoplasms
Alcohol Drinking
Drinking
Life Style
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., ... Ogawa, S. (2019). Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature, 565(7739), 312-317. https://doi.org/10.1038/s41586-018-0811-x

Age-related remodelling of oesophageal epithelia by mutated cancer drivers. / Yokoyama, Akira; Kakiuchi, Nobuyuki; Yoshizato, Tetsuichi; Nannya, Yasuhito; Suzuki, Hiromichi; Takeuchi, Yasuhide; Shiozawa, Yusuke; Sato, Yusuke; Aoki, Kosuke; Kim, Soo Ki; Fujii, Yoichi; Yoshida, Kenichi; Kataoka, Keisuke; Nakagawa, Masahiro M.; Inoue, Yoshikage; Hirano, Tomonori; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Sanada, Masashi; Nishikawa, Yoshitaka; Amanuma, Yusuke; Ohashi, Shinya; Aoyama, Ikuo; Horimatsu, Takahiro; Miyamoto, Shinichi; Tsunoda, Shigeru; Sakai, Yoshiharu; Narahara, Maiko; Brown, J. B.; Sato, Yoshitaka; Sawada, Genta; Mimori, Koshi; Minamiguchi, Sachiko; Haga, Hironori; Seno, Hiroshi; Miyano, Satoru; Makishima, Hideki; Muto, Manabu; Ogawa, Seishi.

In: Nature, Vol. 565, No. 7739, 17.01.2019, p. 312-317.

Research output: Contribution to journalArticle

Yokoyama, A, Kakiuchi, N, Yoshizato, T, Nannya, Y, Suzuki, H, Takeuchi, Y, Shiozawa, Y, Sato, Y, Aoki, K, Kim, SK, Fujii, Y, Yoshida, K, Kataoka, K, Nakagawa, MM, Inoue, Y, Hirano, T, Shiraishi, Y, Chiba, K, Tanaka, H, Sanada, M, Nishikawa, Y, Amanuma, Y, Ohashi, S, Aoyama, I, Horimatsu, T, Miyamoto, S, Tsunoda, S, Sakai, Y, Narahara, M, Brown, JB, Sato, Y, Sawada, G, Mimori, K, Minamiguchi, S, Haga, H, Seno, H, Miyano, S, Makishima, H, Muto, M & Ogawa, S 2019, 'Age-related remodelling of oesophageal epithelia by mutated cancer drivers', Nature, vol. 565, no. 7739, pp. 312-317. https://doi.org/10.1038/s41586-018-0811-x
Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, Suzuki H, Takeuchi Y et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature. 2019 Jan 17;565(7739):312-317. https://doi.org/10.1038/s41586-018-0811-x
Yokoyama, Akira ; Kakiuchi, Nobuyuki ; Yoshizato, Tetsuichi ; Nannya, Yasuhito ; Suzuki, Hiromichi ; Takeuchi, Yasuhide ; Shiozawa, Yusuke ; Sato, Yusuke ; Aoki, Kosuke ; Kim, Soo Ki ; Fujii, Yoichi ; Yoshida, Kenichi ; Kataoka, Keisuke ; Nakagawa, Masahiro M. ; Inoue, Yoshikage ; Hirano, Tomonori ; Shiraishi, Yuichi ; Chiba, Kenichi ; Tanaka, Hiroko ; Sanada, Masashi ; Nishikawa, Yoshitaka ; Amanuma, Yusuke ; Ohashi, Shinya ; Aoyama, Ikuo ; Horimatsu, Takahiro ; Miyamoto, Shinichi ; Tsunoda, Shigeru ; Sakai, Yoshiharu ; Narahara, Maiko ; Brown, J. B. ; Sato, Yoshitaka ; Sawada, Genta ; Mimori, Koshi ; Minamiguchi, Sachiko ; Haga, Hironori ; Seno, Hiroshi ; Miyano, Satoru ; Makishima, Hideki ; Muto, Manabu ; Ogawa, Seishi. / Age-related remodelling of oesophageal epithelia by mutated cancer drivers. In: Nature. 2019 ; Vol. 565, No. 7739. pp. 312-317.
@article{fb2aca1f124a4520bb710fe7edaae754,
title = "Age-related remodelling of oesophageal epithelia by mutated cancer drivers",
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.",
author = "Akira Yokoyama and Nobuyuki Kakiuchi and Tetsuichi Yoshizato and Yasuhito Nannya and Hiromichi Suzuki and Yasuhide Takeuchi and Yusuke Shiozawa and Yusuke Sato and Kosuke Aoki and Kim, {Soo Ki} and Yoichi Fujii and Kenichi Yoshida and Keisuke Kataoka and Nakagawa, {Masahiro M.} and Yoshikage Inoue and Tomonori Hirano and Yuichi Shiraishi and Kenichi Chiba and Hiroko Tanaka and Masashi Sanada and Yoshitaka Nishikawa and Yusuke Amanuma and Shinya Ohashi and Ikuo Aoyama and Takahiro Horimatsu and Shinichi Miyamoto and Shigeru Tsunoda and Yoshiharu Sakai and Maiko Narahara and Brown, {J. B.} and Yoshitaka Sato and Genta Sawada and Koshi Mimori and Sachiko Minamiguchi and Hironori Haga and Hiroshi Seno and Satoru Miyano and Hideki Makishima and Manabu Muto and Seishi Ogawa",
year = "2019",
month = "1",
day = "17",
doi = "10.1038/s41586-018-0811-x",
language = "English",
volume = "565",
pages = "312--317",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7739",

}

TY - JOUR

T1 - Age-related remodelling of oesophageal epithelia by mutated cancer drivers

AU - Yokoyama, Akira

AU - Kakiuchi, Nobuyuki

AU - Yoshizato, Tetsuichi

AU - Nannya, Yasuhito

AU - Suzuki, Hiromichi

AU - Takeuchi, Yasuhide

AU - Shiozawa, Yusuke

AU - Sato, Yusuke

AU - Aoki, Kosuke

AU - Kim, Soo Ki

AU - Fujii, Yoichi

AU - Yoshida, Kenichi

AU - Kataoka, Keisuke

AU - Nakagawa, Masahiro M.

AU - Inoue, Yoshikage

AU - Hirano, Tomonori

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Sanada, Masashi

AU - Nishikawa, Yoshitaka

AU - Amanuma, Yusuke

AU - Ohashi, Shinya

AU - Aoyama, Ikuo

AU - Horimatsu, Takahiro

AU - Miyamoto, Shinichi

AU - Tsunoda, Shigeru

AU - Sakai, Yoshiharu

AU - Narahara, Maiko

AU - Brown, J. B.

AU - Sato, Yoshitaka

AU - Sawada, Genta

AU - Mimori, Koshi

AU - Minamiguchi, Sachiko

AU - Haga, Hironori

AU - Seno, Hiroshi

AU - Miyano, Satoru

AU - Makishima, Hideki

AU - Muto, Manabu

AU - Ogawa, Seishi

PY - 2019/1/17

Y1 - 2019/1/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060173373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060173373&partnerID=8YFLogxK

U2 - 10.1038/s41586-018-0811-x

DO - 10.1038/s41586-018-0811-x

M3 - Article

VL - 565

SP - 312

EP - 317

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7739

ER -