title: Only three driver gene mutations are required for the development of lung and colorectal cancers.
abstract: Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, how many such mutations are required for a normal human cell to progress to an advanced cancer? The best estimates for this number have been provided by mathematical models based on the relation between age and incidence. For example, the classic studies of Nordling [Nordling CO (1953) Br J Cancer 7(1):68-72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1-12] suggest that six or seven sequential mutations are required. Here, we describe a different approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data: incidence data for different groups of patients with the same cancer type were compared with respect to their somatic mutation rates. In two well-documented cancer types (lung and colon adenocarcinomas), we find that only three sequential mutations are required to develop cancer. This conclusion deepens our understanding of the process of carcinogenesis and has important implications for the design of future cancer genome-sequencing efforts.
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, and Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; ctomasetti@jhu.edu vogelbe@jhmi.edu.
authors.forename: Cristian
authors.initials: C
authors.lastname: Tomasetti
authors.affiliation: Cancer Biology Program, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Program for Evolutionary Dynamics, Department of Mathematics, Harvard University, Cambridge, MA 02138;
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215; and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205 ctomasetti@jhu.edu vogelbe@jhmi.edu.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D012907:Smoking / Q000009:adverse effects
keywords: cancer; cancer evolution; cancer incidence; driver mutations; somatic mutation rate