Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 43, Pages 18545-18550Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1010978107
Keywords
genetics; mathematical biology
Categories
Funding
- John Templeton Foundation
- National Science Foundation (NSF)/National Institutes of Health (NIH) [R01GM078986]
- Bill and Melinda Gates Foundation [37874]
- NIH [CA 57345, CA 135877, CA 62924]
- NSF [DBI 0845275]
- National Defense Science and Engineering [32 CFR 168a]
- J. Epstein
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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.
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