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

• Published in: Nature communications Vol. 9; no. 1; pp. 2884 - 11
• Main Authors: Saito, Tomoko, Niida, Atsushi, Uchi, Ryutaro, Hirata, Hidenari, Komatsu, Hisateru, Sakimura, Shotaro, Hayashi, Shuto, Nambara, Sho, Kuroda, Yosuke, Ito, Shuhei, Eguchi, Hidetoshi, Masuda, Takaaki, Sugimachi, Keishi, Tobo, Taro, Nishida, Haruto, Daa, Tsutomu, Chiba, Kenichi, Shiraishi, Yuichi, Yoshizato, Tetsuichi, Kodama, Masaaki, Okimoto, Tadayoshi, Mizukami, Kazuhiro, Ogawa, Ryo, Okamoto, Kazuhisa, Shuto, Mitsutaka, Fukuda, Kensuke, Matsui, Yusuke, Shimamura, Teppei, Hasegawa, Takanori, Doki, Yuichiro, Nagayama, Satoshi, Yamada, Kazutaka, Kato, Mamoru, Shibata, Tatsuhiro, Mori, Masaki, Aburatani, Hiroyuki, Murakami, Kazunari, Suzuki, Yutaka, Ogawa, Seishi, Miyano, Satoru, Mimori, Koshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/67/1504/1885; 631/67/2329; Adenoma; Adenoma - genetics; Adenoma - metabolism; Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein - genetics; Bayes Theorem; Biological Evolution; Cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Disease Progression; Evolution; Evolution, Molecular; Exome; Gene Frequency; Genetic Heterogeneity; Heterogeneity; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Humans; Lesions; multidisciplinary; Mutation; Proto-Oncogene Proteins p21(ras) - genetics; Science; Science (multidisciplinary); Sequence Analysis, DNA; Time Factors; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05226-0

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. Advanced colorectal cancers are characterised by intra-tumour heterogeneity dictated by neutral evolution. Here the authors analyse early colorectal tumours by whole-exome sequencing and find that Darwinian evolution determines the fate of early lesions in colorectal adenoma and carcinoma in situ.