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

Proceedings of the National Academy of Sciences - PNAS, 2015-01, Vol.112 (1), p.118-123 [Peer Reviewed Journal]

Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Jan 6, 2015 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1421839112 ;PMID: 25535351

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  • Title:
    Only three driver gene mutations are required for the development of lung and colorectal cancers
  • Author: Tomasett, Cristiani ; Marchionni, Luigi ; Nowak, Martin A. ; Parmigiani, Giovanni ; Vogelstein, Bert
  • Subjects: Adenocarcinoma - genetics ; Biological Sciences ; Cancer ; Carcinogenesis - genetics ; Colorectal Neoplasms - epidemiology ; Colorectal Neoplasms - genetics ; DNA Mismatch Repair - genetics ; Epidemiology ; Genes ; Humans ; Incidence ; Lung Neoplasms - epidemiology ; Lung Neoplasms - genetics ; Mathematical models ; Mutation ; Mutation - genetics ; Mutation Rate ; Physical Sciences ; Smoking - adverse effects ; Tumors
  • Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2015-01, Vol.112 (1), p.118-123
  • Description: Significance The number of driver events required for human tumorigenesis has remained one of the fundamental issues in cancer research since the seminal studies of Armitage and Doll. This question has become even more important with the recent genome-wide sequencing studies of cancer, whose major goal is the identification of the driver genes responsible for tumor initiation and progression. By using a novel approach that combines conventional epidemiologic studies with genome-wide sequencing data, we show that only three sequential mutations are required to develop lung and colon adenocarcinomas, a number that is lower than what is typically thought to be required for the formation of cancers of these and other organs. This finding has important implications for the design of future cancer genome-sequencing efforts. 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.
  • Publisher: United States: National Academy of Sciences
  • Language: English
  • Identifier: ISSN: 0027-8424
    EISSN: 1091-6490
    DOI: 10.1073/pnas.1421839112
    PMID: 25535351
  • Source: GFMER Free Medical Journals
    MEDLINE
    PubMed Central
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