Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 6; pp. 1999 - 2004
• Main Authors: Tomasetti, Cristian, Vogelstein, Bert, Parmigiani, Giovanni
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.02.2013; National Acad Sciences
• Subjects: Age of Onset; Aging - genetics; Aging - pathology; Biological Sciences; Cancer; Cell Transformation, Neoplastic - genetics; Cocarcinogenesis; Correlation analysis; Correlations; Crypts; Daughter cells; Female; Genetic mutation; Humans; Linear Models; Male; Mathematical Concepts; Mathematical models; Models, Genetic; Mutation; Neoplasms - etiology; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - pathology; Organ Specificity; Passengers; Physical Sciences; Point mutation; Somatic mutation; Stem cells; Stochastic Processes; Tissues; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221068110

Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue’s history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of self-renewing tissues is positively correlated with the age of the patient at diagnosis. Importantly, our analysis indicates that half or more of the somatic mutations in certain tumors of self-renewing tissues occur before the onset of neoplasia. The model also provides a unique way to estimate the in vivo tissue-specific somatic mutation rates in normal tissues directly from the sequencing data of tumors. Our results have substantial implications for the interpretation of the large number of genome-wide cancer studies now being undertaken.