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Research Article

Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations

Andrii I. Rozhok and James DeGregori
  1. aDepartment of Biochemistry and Molecular Genetics,
  2. bIntegrated Department of Immunology,
  3. cDepartment of Pediatrics, and
  4. dSection of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045

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PNAS July 21, 2015 112 (29) 8914-8921; first published July 21, 2015; https://doi.org/10.1073/pnas.1501713112
Andrii I. Rozhok
aDepartment of Biochemistry and Molecular Genetics,
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James DeGregori
aDepartment of Biochemistry and Molecular Genetics,
bIntegrated Department of Immunology,
cDepartment of Pediatrics, and
dSection of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045
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  • For correspondence: james.degregori@ucdenver.edu
  1. Edited by Francisco J. Ayala, University of California, Irvine, CA, and approved April 3, 2015 (received for review February 11, 2015)

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Abstract

Our understanding of cancer has greatly advanced since 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] put forth the multistage model of carcinogenesis. However, a number of observations remain poorly understood from the standpoint of this paradigm in its contemporary state. These observations include the similar age-dependent exponential rise in incidence of cancers originating from stem/progenitor pools differing drastically in size, age-dependent cell division profiles, and compartmentalization. This common incidence pattern is characteristic of cancers requiring different numbers of oncogenic mutations, and it scales to very divergent life spans of mammalian species. Also, bigger mammals with larger underlying stem cell pools are not proportionally more prone to cancer, an observation known as Peto’s paradox. Here, we present a number of factors beyond the occurrence of oncogenic mutations that are unaccounted for in the current model of cancer development but should have significant impacts on cancer incidence. Furthermore, we propose a revision of the current understanding for how oncogenic and other functional somatic mutations affect cellular fitness. We present evidence, substantiated by evolutionary theory, demonstrating that fitness is a dynamic environment-dependent property of a phenotype and that oncogenic mutations should have vastly different fitness effects on somatic cells dependent on the tissue microenvironment in an age-dependent manner. Combined, this evidence provides a firm basis for understanding the age-dependent incidence of cancers as driven by age-altered systemic processes regulated above the cell level.

  • somatic evolution
  • cancer
  • aging
  • oncogenic mutations
  • fitness

Footnotes

  • ↵1To whom correspondence should be addressed. Email: james.degregori{at}ucdenver.edu.
  • Author contributions: A.I.R. and J.D. wrote the paper.

  • The authors declare no conflict of interest.

  • This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “In the Light of Evolution IX: Clonal Reproduction: Alternatives to Sex,” held January 9–10, 2015, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and video recordings of most presentations are available on the NAS website at www.nasonline.org/ILE_IX_Clonal_Reproduction.

  • This article is a PNAS Direct Submission.

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Toward an evolutionary model of cancer
Andrii I. Rozhok, James DeGregori
Proceedings of the National Academy of Sciences Jul 2015, 112 (29) 8914-8921; DOI: 10.1073/pnas.1501713112

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Toward an evolutionary model of cancer
Andrii I. Rozhok, James DeGregori
Proceedings of the National Academy of Sciences Jul 2015, 112 (29) 8914-8921; DOI: 10.1073/pnas.1501713112
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  • Biological Sciences
  • Evolution
Proceedings of the National Academy of Sciences: 112 (29)
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  • Article
    • Abstract
    • Fitness Effects of Mutations
    • Fitness in SCs
    • Tissue Architecture: Drift vs. Selection
    • SC Divisions and the Odds of Accumulating Multiple Oncogenic Mutations
    • Conclusions
    • Acknowledgments
    • Footnotes
    • References
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