Accumulation of Driver and Passenger Mutations During Tumor Progression

View/ Open
Author
Antal, Tibor
Ohtsuki, Hisashi
Carter, Hannah
Kim, Dewey
Chen, Sining
Karchin, Rachel
Kinzler, Kenneth
Vogelstein, Bert
Published Version
https://doi.org/10.1073/pnas.1010978107Metadata
Show full item recordCitation
Bozic, Ivana, Tibor Antal, Hisashi Ohtsuki, Hannah Carter, Dewey Kim, Sining Chen, Rachel Karchin, Kenneth W. Kinzler, Bert Vogelstein, and Martin A. Nowak. 2010. Accumulation of driver and passenger mutations during tumor progression. Proceedings of the National Academy of Sciences 107(43): 18545.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 novel 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, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research.Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:5351640
Collections
- FAS Scholarly Articles [18172]
Contact administrator regarding this item (to report mistakes or request changes)