Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation
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 mutatio...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 6; pp. 1999 - 2004 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.02.2013
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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. [PUBLICATION ABSTRACT] |
| Author | Vogelstein, Bert Tomasetti, Cristian Parmigiani, Giovanni |
| Author_xml | – sequence: 1 givenname: Cristian surname: Tomasetti fullname: Tomasetti, Cristian – sequence: 2 givenname: Bert surname: Vogelstein fullname: Vogelstein, Bert – sequence: 3 givenname: Giovanni surname: Parmigiani fullname: Parmigiani, Giovanni |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23345422$$D View this record in MEDLINE/PubMed |
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| Snippet | Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or... |
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| SubjectTerms | 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 |
| Title | Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation |
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