Accumulation of driver and passenger mutations during tumor progression

Ivana Bozic, Tibor Antal, Hisashi Ohtsuki, Hannah Carter, Dewey Kim, Sining Chen, Rachel Karchin, Kenneth W. Kinzler, Bert Bogelstein, Martin A. Nowak

Research output: Contribution to journalArticlepeer-review

Abstract

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small-0.004 +/- 0.0004-and has major implications for experimental cancer research.

Original languageEnglish
Pages (from-to)18545-18550
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number43
DOIs
Publication statusPublished - 26 Oct 2010

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