title: Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.
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.
authors.affiliation: Molecular Pathology, IRCCS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genoa, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Amaro
authors.affiliation: Medical Oncology, IRCCS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Chiara
authors.affiliation: Molecular Pathology, IRCCS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132, Genoa, Italy. patologia.molecolare.integrata@gmail.com.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
mesh_terms: D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation
keywords: Big bang; Carcinogenesis; Chromosome instability; Colorectal cancer; Microsatellite instability; Tumor evolution; Tumor heterogeneity