Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics
  • Biological Evolution*
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic*
  • Exome
  • Female
  • Founder Effect
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Polymorphism, Single Nucleotide

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human

Grants and funding

The present study was supported in part by the following grants and foundation; CREST, Japan Science and Technology Agency (JST), the Funding Program for Next Generation World-Leading Researchers (LS094), Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, grant number 25861199, Grants-in-Aid for Scientific Research on Innovative Areas of Ministry of Education, Culture, Sports, Science, and Technology "Systems Cancer Research" (4201), and The MEXT Strategic Programs on Innovative Research "Supercomputational Life Science", and the YASUDA Medical Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.