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

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.

[1]  Andrea Sottoriva,et al.  Defining Stem Cell Dynamics in Models of Intestinal Tumor Initiation , 2013, Science.

[2]  S. Elledge,et al.  Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome , 2013, Cell.

[3]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[4]  E. Lander,et al.  Lessons from the Cancer Genome , 2013, Cell.

[5]  Cancer Risks for MLH1 and MSH2 Mutation Carriers , 2013, Human mutation.

[6]  Giovanni Parmigiani,et al.  Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation , 2013, Proceedings of the National Academy of Sciences.

[7]  Prabhat Jha,et al.  21st-century hazards of smoking and benefits of cessation in the United States. , 2013, The New England journal of medicine.

[8]  Z. Agur,et al.  Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database , 2012, American journal of hematology.

[9]  M. Marinus,et al.  DNA Mismatch Repair , 2012, EcoSal Plus.

[10]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[11]  K. Polyak,et al.  Intra-tumour heterogeneity: a looking glass for cancer? , 2012, Nature Reviews Cancer.

[12]  Peter A. Jones,et al.  A decade of exploring the cancer epigenome — biological and translational implications , 2011, Nature Reviews Cancer.

[13]  Matej Horvat,et al.  Microsatellite instability in colorectal cancer , 2011, Radiology and oncology.

[14]  D. Levy,et al.  Role of symmetric and asymmetric division of stem cells in developing drug resistance , 2010, Proceedings of the National Academy of Sciences.

[15]  Richard Durrett,et al.  Evolution of Resistance and Progression to Disease during Clonal Expansion of Cancer , 2009 .

[16]  M. Stratton,et al.  The cancer genome , 2009, Nature.

[17]  S. Frank Dynamics of Cancer: Incidence, Inheritance, and Evolution , 2007 .

[18]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[19]  Steven A. Frank,et al.  Dynamics of Cancer , 2007 .

[20]  E. Feuer,et al.  SEER Cancer Statistics Review, 1975-2003, National Cancer Institute. Bethesda, MD, , 2006 .

[21]  Il-Jin Kim,et al.  [Hereditary colorectal cancer]. , 2005, The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi.

[22]  R Doll,et al.  Mortality from cancer in relation to smoking: 50 years observations on British doctors , 2005, British Journal of Cancer.

[23]  P. Armitage,et al.  The Age Distribution of Cancer and a Multi-stage Theory of Carcinogenesis , 1954, British Journal of Cancer.

[24]  E Georg Luebeck,et al.  Multistage carcinogenesis and the incidence of colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Knudson,et al.  Two genetic hits (more or less) to cancer , 2001, Nature Reviews Cancer.

[26]  Richard Doll,et al.  Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies , 2000, BMJ : British Medical Journal.

[27]  A. Jackson,et al.  The mutation rate and cancer. , 1998, Genetics.

[28]  M. Little,et al.  Are two mutations sufficient to cause cancer? Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll. , 1995, Biometrics.

[29]  E G Luebeck,et al.  Multistage carcinogenesis: population-based model for colon cancer. , 1992, Journal of the National Cancer Institute.

[30]  S H Moolgavkar,et al.  A stochastic two-stage model for cancer risk assessment. I. The hazard function and the probability of tumor. , 1988, Risk analysis : an official publication of the Society for Risk Analysis.

[31]  R. Gale,et al.  Chronic myeloid leukemia. , 1992, The American journal of medicine.

[32]  S. Baylin,et al.  Tumor cell heterogeneity : origins and implications , 1982 .

[33]  A. Knudson Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Nordling A New Theory on the Cancer-inducing Mechanism , 1953, British Journal of Cancer.

[35]  Nordling Co A New Theory on the Cancer-inducing Mechanism , 1953 .

[36]  R. Doll,et al.  Smoking and Carcinoma of the Lung , 1950, Acta - Unio Internationalis Contra Cancrum.

[37]  R. Doll,et al.  Smoking and carcinoma of the lung; preliminary report. , 1950, British medical journal.