Genetic progression and the waiting time to cancer

Niko Beerenwinkel, Tibor Antal, David Dingli, Arne Traulsen, Kenneth W. Kinzler, Victor E. Velculescu, Bert Vogelstein, Martin A. Nowak

Research output: Contribution to journalArticle

269 Scopus citations

Abstract

Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjöblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth.

Original languageEnglish (US)
Pages (from-to)2239-2246
Number of pages8
JournalPLoS computational biology
Volume3
Issue number11
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

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    Beerenwinkel, N., Antal, T., Dingli, D., Traulsen, A., Kinzler, K. W., Velculescu, V. E., Vogelstein, B., & Nowak, M. A. (2007). Genetic progression and the waiting time to cancer. PLoS computational biology, 3(11), 2239-2246. https://doi.org/10.1371/journal.pcbi.0030225