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 and Koshi Mimori ()
Additional contact information
Tomoko Saito: Kyushu University Beppu Hospital
Atsushi Niida: The University of Tokyo
Ryutaro Uchi: Kyushu University Beppu Hospital
Hidenari Hirata: Kyushu University Beppu Hospital
Hisateru Komatsu: Kyushu University Beppu Hospital
Shotaro Sakimura: Kyushu University Beppu Hospital
Shuto Hayashi: The University of Tokyo
Sho Nambara: Kyushu University Beppu Hospital
Yosuke Kuroda: Kyushu University Beppu Hospital
Shuhei Ito: Kyushu University Beppu Hospital
Hidetoshi Eguchi: Kyushu University Beppu Hospital
Takaaki Masuda: Kyushu University Beppu Hospital
Keishi Sugimachi: Kyushu University Beppu Hospital
Taro Tobo: Kyushu University Beppu Hospital
Haruto Nishida: Oita University Hospital
Tsutomu Daa: Oita University Hospital
Kenichi Chiba: The University of Tokyo
Yuichi Shiraishi: The University of Tokyo
Tetsuichi Yoshizato: Kyoto University
Masaaki Kodama: Oita University Hospital
Tadayoshi Okimoto: Oita University Hospital
Kazuhiro Mizukami: Oita University Hospital
Ryo Ogawa: Oita University Hospital
Kazuhisa Okamoto: Oita University Hospital
Mitsutaka Shuto: Oita University Hospital
Kensuke Fukuda: Oita University Hospital
Yusuke Matsui: Nagoya University Graduate School of Medicine
Teppei Shimamura: Nagoya University Graduate School of Medicine
Takanori Hasegawa: The University of Tokyo
Yuichiro Doki: Osaka University
Satoshi Nagayama: Cancer Institute Hospital, Japanese Foundation for Cancer Research
Kazutaka Yamada: Takano Hospital
Mamoru Kato: National Cancer Center Research Institute
Tatsuhiro Shibata: National Cancer Center Research Institute
Masaki Mori: Osaka University
Hiroyuki Aburatani: The University of Tokyo
Kazunari Murakami: Oita University Hospital
Yutaka Suzuki: The University of Tokyo
Seishi Ogawa: Kyoto University
Satoru Miyano: The University of Tokyo
Koshi Mimori: Kyushu University Beppu Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05226-0

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