Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang

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11 Citations (Scopus)

Abstract

Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial–mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalCANCER AND METASTASIS REVIEW
DOIs
Publication statusAccepted/In press - Mar 7 2016

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Molecular Evolution
Genomic Instability
Colorectal Neoplasms
Chromosomal Instability
Microsatellite Instability
Carcinogenesis
Clone Cells
Mutation
CpG Islands
DNA Mismatch Repair
Neoplastic Stem Cells
Genomics
Methylation
Neoplasms
Phenotype
Genes

Keywords

  • Big bang
  • Carcinogenesis
  • Chromosome instability
  • Colorectal cancer
  • Microsatellite instability
  • Tumor evolution
  • Tumor heterogeneity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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abstract = "Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial–mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.",
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AU - Pfeffer, Ulrich

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