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PLoS Genet. 2016 Feb 18;12(2):e1005778. doi: 10.1371/journal.pgen.1005778. eCollection 2016 Feb.

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

Author information

1
Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
2
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
3
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
4
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
5
Department of Surgery, Iwate Medical University, Morioka, Japan.
6
Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
7
Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
8
Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
9
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
10
Department of Surgery, Omori Red Cross Hospital, Tokyo, Japan.
11
Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
12
Department of Surgery, Takano Hospital, Kumamoto, Japan.
13
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
14
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
15
Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
16
Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa-shi, Chiba, Japan.
17
Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan.

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.

PMID:
26890883
PMCID:
PMC4758664
DOI:
10.1371/journal.pgen.1005778
[Indexed for MEDLINE]
Free PMC Article

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