Only three driver gene mutations are required for the development of lung and colorectal cancers

Cristian Tomasetti, Luigi Marchionni, Martin A. Nowak, Giovanni Parmigiani, Bert Vogelstein

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)118-123
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number1
DOIs
StatePublished - Jan 6 2015

Keywords

  • Cancer
  • Cancer evolution
  • Cancer incidence
  • Driver mutations
  • Somatic mutation rate

ASJC Scopus subject areas

  • General

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