A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer

Tomoko Saito; Atsushi Niida; Ryutaro Uchi; Hidenari Hirata; Hisateru Komatsu; Shotaro Sakimura; Shuto Hayashi; Sho Nambara; Yosuke Kuroda; Shuhei Ito; Hidetoshi Eguchi; Takaaki Masuda; Keishi Sugimachi; Taro Tobo; Haruto Nishida; Tsutomu Daa; Kenichi Chiba; Yuichi Shiraishi; Tetsuichi Yoshizato; Masaaki Kodama; Tadayoshi Okimoto; Kazuhiro Mizukami; Ryo Ogawa; Kazuhisa Okamoto; Mitsutaka Shuto; Kensuke Fukuda; Yusuke Matsui; Teppei Shimamura; Takanori Hasegawa; Yuichiro Doki; Satoshi Nagayama; Kazutaka Yamada; Mamoru Kato; Tatsuhiro Shibata; Masaki Mori; Hiroyuki Aburatani; Kazunari Murakami; Yutaka Suzuki; Seishi Ogawa; Satoru Miyano; Koshi Mimori

doi:10.1038/s41467-018-05226-0

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer

Tomoko Saito, Atsushi Niida, Ryutaro Uchi, Hidenari Hirata, Hisateru Komatsu, Shotaro Sakimura, Shuto Hayashi, Sho Nambara, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Takaaki Masuda, Keishi Sugimachi, Taro Tobo, Haruto Nishida, Tsutomu Daa, Kenichi Chiba, Yuichi Shiraishi, Tetsuichi Yoshizato, Masaaki KodamaTadayoshi Okimoto, Kazuhiro Mizukami, Ryo Ogawa, Kazuhisa Okamoto, Mitsutaka Shuto, Kensuke Fukuda, Yusuke Matsui, Teppei Shimamura, Takanori Hasegawa, Yuichiro Doki, Satoshi Nagayama, Kazutaka Yamada, Mamoru Kato, Tatsuhiro Shibata, Masaki Mori, Hiroyuki Aburatani, Kazunari Murakami, Yutaka Suzuki, Seishi Ogawa, Satoru Miyano, Koshi Mimori

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Abstract

Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

Original language	English
Article number	2884
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05226-0
Publication status	Published - Dec 1 2018

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

UN SDGs

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Saito, T., Niida, A., Uchi, R., Hirata, H., Komatsu, H., Sakimura, S., Hayashi, S., Nambara, S., Kuroda, Y., Ito, S., Eguchi, H., Masuda, T., Sugimachi, K., Tobo, T., Nishida, H., Daa, T., Chiba, K., Shiraishi, Y., Yoshizato, T., ... Mimori, K. (2018). A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer. Nature communications, 9(1), Article 2884. https://doi.org/10.1038/s41467-018-05226-0

Saito, T, Niida, A, Uchi, R, Hirata, H, Komatsu, H, Sakimura, S, Hayashi, S, Nambara, S, Kuroda, Y, Ito, S, Eguchi, H, Masuda, T, Sugimachi, K, Tobo, T, Nishida, H, Daa, T, Chiba, K, Shiraishi, Y, Yoshizato, T, Kodama, M, Okimoto, T, Mizukami, K, Ogawa, R, Okamoto, K, Shuto, M, Fukuda, K, Matsui, Y, Shimamura, T, Hasegawa, T, Doki, Y, Nagayama, S, Yamada, K, Kato, M, Shibata, T, Mori, M, Aburatani, H, Murakami, K, Suzuki, Y, Ogawa, S, Miyano, S & Mimori, K 2018, 'A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer', Nature communications, vol. 9, no. 1, 2884. https://doi.org/10.1038/s41467-018-05226-0

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title = "A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer",

abstract = "Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.",

author = "Tomoko Saito and Atsushi Niida and Ryutaro Uchi and Hidenari Hirata and Hisateru Komatsu and Shotaro Sakimura and Shuto Hayashi and Sho Nambara and Yosuke Kuroda and Shuhei Ito and Hidetoshi Eguchi and Takaaki Masuda and Keishi Sugimachi and Taro Tobo and Haruto Nishida and Tsutomu Daa and Kenichi Chiba and Yuichi Shiraishi and Tetsuichi Yoshizato and Masaaki Kodama and Tadayoshi Okimoto and Kazuhiro Mizukami and Ryo Ogawa and Kazuhisa Okamoto and Mitsutaka Shuto and Kensuke Fukuda and Yusuke Matsui and Teppei Shimamura and Takanori Hasegawa and Yuichiro Doki and Satoshi Nagayama and Kazutaka Yamada and Mamoru Kato and Tatsuhiro Shibata and Masaki Mori and Hiroyuki Aburatani and Kazunari Murakami and Yutaka Suzuki and Seishi Ogawa and Satoru Miyano and Koshi Mimori",

note = "Funding Information: This project was supported by JSPS KAKENHI (16K19107, 15H05707), Grant-in-Aid for Scientific Research on Innovative Areas (15H05912), Priority Issue on Post-K computer (hp170227, hp160219), and Research Grant of the Princess Takamatsu Cancer Research Fund, and partially supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) and Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development, AMED. This research used the supercomputing resource provided by the Human Genome Center, Institute of Medical Science, University of Tokyo (http://sc.hgc.jp/shirokane.html). We thank the members of Department of Gastroenterology of Oita University and Department of Surgery of Kyushu University Beppu Hospital for sample collection and useful discussion; R. Yoshida for useful discussion; and K. Oda, M. Kasagi, S. Sakuma, N. Mishima, and T. Kawano for their assistance. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41467-018-05226-0",

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AU - Saito, Tomoko

AU - Niida, Atsushi

AU - Uchi, Ryutaro

AU - Hirata, Hidenari

AU - Komatsu, Hisateru

AU - Sakimura, Shotaro

AU - Hayashi, Shuto

AU - Nambara, Sho

AU - Kuroda, Yosuke

AU - Ito, Shuhei

AU - Eguchi, Hidetoshi

AU - Masuda, Takaaki

AU - Sugimachi, Keishi

AU - Tobo, Taro

AU - Nishida, Haruto

AU - Daa, Tsutomu

AU - Chiba, Kenichi

AU - Shiraishi, Yuichi

AU - Yoshizato, Tetsuichi

AU - Kodama, Masaaki

AU - Okimoto, Tadayoshi

AU - Mizukami, Kazuhiro

AU - Ogawa, Ryo

AU - Okamoto, Kazuhisa

AU - Shuto, Mitsutaka

AU - Fukuda, Kensuke

AU - Matsui, Yusuke

AU - Shimamura, Teppei

AU - Hasegawa, Takanori

AU - Doki, Yuichiro

AU - Nagayama, Satoshi

AU - Yamada, Kazutaka

AU - Kato, Mamoru

AU - Shibata, Tatsuhiro

AU - Mori, Masaki

AU - Aburatani, Hiroyuki

AU - Murakami, Kazunari

AU - Suzuki, Yutaka

AU - Ogawa, Seishi

AU - Miyano, Satoru

AU - Mimori, Koshi

N1 - Funding Information: This project was supported by JSPS KAKENHI (16K19107, 15H05707), Grant-in-Aid for Scientific Research on Innovative Areas (15H05912), Priority Issue on Post-K computer (hp170227, hp160219), and Research Grant of the Princess Takamatsu Cancer Research Fund, and partially supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) and Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development, AMED. This research used the supercomputing resource provided by the Human Genome Center, Institute of Medical Science, University of Tokyo (http://sc.hgc.jp/shirokane.html). We thank the members of Department of Gastroenterology of Oita University and Department of Surgery of Kyushu University Beppu Hospital for sample collection and useful discussion; R. Yoshida for useful discussion; and K. Oda, M. Kasagi, S. Sakuma, N. Mishima, and T. Kawano for their assistance. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

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A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer

Abstract

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