title: Accumulation of driver and passenger mutations during tumor progression.
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.
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bozic
authors.forename: Tibor
authors.initials: T
authors.lastname: Antal
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohtsuki
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.forename: Dewey
authors.initials: D
authors.lastname: Kim
authors.forename: Sining
authors.initials: S
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000209:etiology / Q000235:genetics / Q000473:pathology; D003198:Computer Simulation; D018450:Disease Progression; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D005828:Genetics, Population; D023281:Genomics; D006801:Humans; D008957:Models, Genetic; D008967:Molecular Biology; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009385:Neoplastic Processes; D009857:Oncogenes; D013269:Stochastic Processes; D013997:Time Factors