Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

• Published in: PLoS genetics Vol. 12; no. 2; p. e1005778
• Main Authors: Uchi, Ryutaro, Takahashi, Yusuke, Niida, Atsushi, Shimamura, Teppei, Hirata, Hidenari, Sugimachi, Keishi, Sawada, Genta, Iwaya, Takeshi, Kurashige, Junji, Shinden, Yoshiaki, Iguchi, Tomohiro, Eguchi, Hidetoshi, Chiba, Kenichi, Shiraishi, Yuichi, Nagae, Genta, Yoshida, Kenichi, Nagata, Yasunobu, Haeno, Hiroshi, Yamamoto, Hirofumi, Ishii, Hideshi, Doki, Yuichiro, Iinuma, Hisae, Sasaki, Shin, Nagayama, Satoshi, Yamada, Kazutaka, Yachida, Shinichi, Kato, Mamoru, Shibata, Tatsuhiro, Oki, Eiji, Saeki, Hiroshi, Shirabe, Ken, Oda, Yoshinao, Maehara, Yoshihiko, Komune, Shizuo, Mori, Masaki, Suzuki, Yutaka, Yamamoto, Ken, Aburatani, Hiroyuki, Ogawa, Seishi, Miyano, Satoru, Mimori, Koshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.02.2016; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; Aging - genetics; Biological Evolution; Biology and life sciences; Cancer metastasis; Class I Phosphatidylinositol 3-Kinases; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; CpG Islands; DNA Methylation; Epigenesis, Genetic; Evolutionary adaptation; Exome; Female; Founder Effect; Gene mutation; Genetic aspects; Health aspects; Humans; Male; Medical research; Medicine and Health Sciences; Middle Aged; Models, Biological; Mutation; Phosphatidylinositol 3-Kinases - genetics; Polymorphism, Single Nucleotide; Research and Analysis Methods; Studies
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005778

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.