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

2018; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41467-018-05226-0

2041-1723

Tomoko Saito, Atsushi Niida, Ryutaro Uchi, Hidenari Hirata, Hisateru Komatsu, Shotaro Sakimura, Shuto Hayashi, Sho Nambara, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Takaaki Masuda, K 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,

Evolution and Genetic Dynamics

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.