Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

• DOI: 10.1371/journal.pgen.1005778
• Publication Date: 2016-02-18T21:28:24Z
• Authors: Ryutaro Uchi; Yusuke Takahashi; Atsushi Niida; Teppei Shimamura; Hidenari Hirata; Keishi Sugimachi; Genta Sawada; Takeshi Iwaya; Junji Kurashige; Yoshiaki Shinden; Tomohiro Iguchi; Hidetoshi Eguchi; Kenichi Chiba; Yuichi Shiraishi; Genta Nagae; Kenichi Yoshida; Yasunobu Nagata; Hiroshi Haeno; Hirofumi Yamamoto; Hideshi Ishii; Yuichiro Doki; Hisae Iinuma; Shin Sasaki; Satoshi Nagayama; Kazutaka Yamada; Shinichi Yachida; Mamoru Kato; Tatsuhiro Shibata; Eiji Oki; Hiroshi Saeki; Ken Shirabe; Yoshinao Oda; Yoshihiko Maehara; Shizuo Komune; Masaki Mori; Yutaka Suzuki; Ken Yamamoto; Hiroyuki Aburatani; Seishi Ogawa; Satoru Miyano; Koshi Mimori
• Keywords: Male; 0301 basic medicine; Aging; Class I Phosphatidylinositol 3-Kinases; QH426-470; Models, Biological; Polymorphism, Single Nucleotide; Epigenesis, Genetic; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Genetics; Humans; Exome; Aged; Aged, 80 and over; DNA Methylation; Middle Aged; Biological Evolution; Founder Effect; 3. Good health; Mutation; CpG Islands; Female; Colorectal Neoplasms; Research Article

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.