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Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 2003 Jun 7;270(1520):1183–1191. doi: 10.1098/rspb.2003.2351

The population genetics of multistage carcinogenesis.

Leonard Nunney 1
PMCID: PMC1691357  PMID: 12816658

Abstract

Despite the many successes of cancer research, we lack the framework necessary to predict the ratio of familial (inherited) to sporadic (non-inherited) cancers. An evolutionary model of multistage carcinogenesis provides this framework by demonstrating that the number of tumour suppressor loci (TSLs) preventing cancer in a given tissue is expected to depend upon the tissue's vulnerability to pre-reproductive somatic mutation. Since this vulnerability increases with tissue size, single gene control of human cancer may be restricted to retinoblastoma, a cancer of the tiny embryonic retina. The model is used to estimate the frequency of mutant alleles causing inherited cancers, based on the population genetics of the mutation-selection balance between new mutations arising and selection that eliminates them. For each specific cancer, this balance is determined by the effectiveness with which pre-reproductive cancer is suppressed in the non-mutant genotype characteristic of that population. Effectiveness depends on an interaction between the number of TSLs suppressing the cancer and factors determining the tissue-wide somatic mutation rate, such as tissue size and number of pre-reproductive cell divisions. The model predicts that the commonest pre-reproductive cancers will have the lowest proportion of familial cases, and that cancers associated with the most TSLs will have the highest post-reproductive incidence but no elevated pre-reproductive risk (a pattern seen in human epithelial cancers).

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Selected References

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  1. ARMITAGE P., DOLL R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954 Mar;8(1):1–12. doi: 10.1038/bjc.1954.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bardelli A., Cahill D. P., Lederer G., Speicher M. R., Kinzler K. W., Vogelstein B., Lengauer C. Carcinogen-specific induction of genetic instability. Proc Natl Acad Sci U S A. 2001 Apr 10;98(10):5770–5775. doi: 10.1073/pnas.081082898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cahill D. P., Kinzler K. W., Vogelstein B., Lengauer C. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999 Dec;9(12):M57–M60. [PubMed] [Google Scholar]
  4. Cairns J. Mutation selection and the natural history of cancer. Nature. 1975 May 15;255(5505):197–200. doi: 10.1038/255197a0. [DOI] [PubMed] [Google Scholar]
  5. DePinho R. A. The age of cancer. Nature. 2000 Nov 9;408(6809):248–254. doi: 10.1038/35041694. [DOI] [PubMed] [Google Scholar]
  6. Dollé M. E., Snyder W. K., Gossen J. A., Lohman P. H., Vijg J. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8403–8408. doi: 10.1073/pnas.97.15.8403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Frank S. A. Mutual policing and repression of competition in the evolution of cooperative groups. Nature. 1995 Oct 12;377(6549):520–522. doi: 10.1038/377520a0. [DOI] [PubMed] [Google Scholar]
  8. Gregori Giovanni, Hanin Leonid, Luebeck Georg, Moolgavkar Suresh, Yakovlev Andrei. Testing goodness of fit for stochastic models of carcinogenesis. Math Biosci. 2002 Jan;175(1):13–29. doi: 10.1016/s0025-5564(01)00088-8. [DOI] [PubMed] [Google Scholar]
  9. Hanahan D., Weinberg R. A. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57–70. doi: 10.1016/s0092-8674(00)81683-9. [DOI] [PubMed] [Google Scholar]
  10. Hethcote H. W., Knudson A. G., Jr Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci U S A. 1978 May;75(5):2453–2457. doi: 10.1073/pnas.75.5.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoeijmakers J. H. Genome maintenance mechanisms for preventing cancer. Nature. 2001 May 17;411(6835):366–374. doi: 10.1038/35077232. [DOI] [PubMed] [Google Scholar]
  12. Huttley G. A., Jakobsen I. B., Wilson S. R., Easteal S. How important is DNA replication for mutagenesis? Mol Biol Evol. 2000 Jun;17(6):929–937. doi: 10.1093/oxfordjournals.molbev.a026373. [DOI] [PubMed] [Google Scholar]
  13. Jones P. A., Laird P. W. Cancer epigenetics comes of age. Nat Genet. 1999 Feb;21(2):163–167. doi: 10.1038/5947. [DOI] [PubMed] [Google Scholar]
  14. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Knudson A. G., Jr, Strong L. C. Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet. 1972 Sep;24(5):514–532. [PMC free article] [PubMed] [Google Scholar]
  16. Loeb L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 1991 Jun 15;51(12):3075–3079. [PubMed] [Google Scholar]
  17. McKean K. A., Zuk M. An evolutionary perspective on signaling in behavior and immunology. Naturwissenschaften. 1995 Nov;82(11):509–516. doi: 10.1007/BF01134486. [DOI] [PubMed] [Google Scholar]
  18. Michod R. E. Cooperation and conflict in the evolution of individuality. II. Conflict mediation. Proc Biol Sci. 1996 Jul 22;263(1372):813–822. doi: 10.1098/rspb.1996.0121. [DOI] [PubMed] [Google Scholar]
  19. Moolgavkar S. H. Carcinogenesis modeling: from molecular biology to epidemiology. Annu Rev Public Health. 1986;7:151–169. doi: 10.1146/annurev.pu.07.050186.001055. [DOI] [PubMed] [Google Scholar]
  20. Moolgavkar S. H., Luebeck E. G. Multistage carcinogenesis: population-based model for colon cancer. J Natl Cancer Inst. 1992 Apr 15;84(8):610–618. doi: 10.1093/jnci/84.8.610. [DOI] [PubMed] [Google Scholar]
  21. NORDLING C. O. A new theory on cancer-inducing mechanism. Br J Cancer. 1953 Mar;7(1):68–72. doi: 10.1038/bjc.1953.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nowak M. A., Boerlijst M. C., Cooke J., Smith J. M. Evolution of genetic redundancy. Nature. 1997 Jul 10;388(6638):167–171. doi: 10.1038/40618. [DOI] [PubMed] [Google Scholar]
  23. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
  24. Nunney L. Lineage selection and the evolution of multistage carcinogenesis. Proc Biol Sci. 1999 Mar 7;266(1418):493–498. doi: 10.1098/rspb.1999.0664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nunney L. The influence of age structure and fecundity on effective population size. Proc Biol Sci. 1991 Oct 22;246(1315):71–76. doi: 10.1098/rspb.1991.0126. [DOI] [PubMed] [Google Scholar]
  26. Orr-Weaver T. L., Weinberg R. A. A checkpoint on the road to cancer. Nature. 1998 Mar 19;392(6673):223–224. doi: 10.1038/32520. [DOI] [PubMed] [Google Scholar]
  27. Phillips P. C., Johnson N. A. The population genetics of synthetic lethals. Genetics. 1998 Sep;150(1):449–458. doi: 10.1093/genetics/150.1.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ponder B. A. Cancer genetics. Nature. 2001 May 17;411(6835):336–341. doi: 10.1038/35077207. [DOI] [PubMed] [Google Scholar]
  29. Stewart S. A., Weinberg R. A. Telomerase and human tumorigenesis. Semin Cancer Biol. 2000 Dec;10(6):399–406. doi: 10.1006/scbi.2000.0339. [DOI] [PubMed] [Google Scholar]
  30. Tautz D. Redundancies, development and the flow of information. Bioessays. 1992 Apr;14(4):263–266. doi: 10.1002/bies.950140410. [DOI] [PubMed] [Google Scholar]
  31. Tomlinson I., Bodmer W. Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nat Med. 1999 Jan;5(1):11–12. doi: 10.1038/4687. [DOI] [PubMed] [Google Scholar]
  32. Wright S. Evolution in Mendelian Populations. Genetics. 1931 Mar;16(2):97–159. doi: 10.1093/genetics/16.2.97. [DOI] [PMC free article] [PubMed] [Google Scholar]

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