title: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.
abstract: 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.
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.affiliation: Department of Surgery, Iwate Medical University, Morioka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shinden
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haeno
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Iinuma
authors.affiliation: Department of Surgery, Omori Red Cross Hospital, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagayama
authors.affiliation: Department of Surgery, Takano Hospital, Kumamoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saeki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.affiliation: Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Komune
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa-shi, Chiba, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D005075:Biological Evolution; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D059472:Exome; D005260:Female; D018703:Founder Effect; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human