IJE Advance Access originally published online on September 20, 2006
International Journal of Epidemiology 2006 35(5):1161-1162; doi:10.1093/ije/dyl187
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© The Author 2006; all rights reserved.
Commentary |
Commentary: Cancer—evolution within
Institute of Basic Medical Science, Faculty of Medicine, PO Box 1018 Blindern, University of Oslo, NO-0315 Oslo, Norway
E-mail: jbreivik{at}medisin.uio.no
According to the current paradigm, cancer is a genetic disease caused the by accumulation of mutations leading to breakdown of growth regulatory mechanisms. Concomitantly, an equally important paradigm states that cancer is an environmental disease caused by factors like smoking, diet, and radiation. The connection between these contrasting perspectives is commonly perceived as a linear causation: environments cause mutations and mutations cause cancer. Despite its apparent logic, however, there is growing awareness that this level of reasoning represents an inadequate basis for modelling carcinogenesis. Genes and mutations can only be understood in the context of their environment. The environment not only induces mutations but it also continuously determines their fate and significance by means of natural selection. ‘Nothing in biology makes sense except in the light of evolution’ and as elaborated by Vineis and Berwick in this issue of the International Journal of Epidemiology,1 the reciprocal dynamics of Darwinian evolution provides a unique framework for understanding cancer.
Gaudernack and I have previously demonstrated how epidemiological, anatomical, biochemical, and genetic data related to colorectal cancer may be regarded in the light of evolutionary dynamics.2 This model makes unique predictions about genetic instability3 and has been explicitly confirmed by in vitro4 and in vivo5 experiments. Vineis and Berwick demonstrate how a similar approach may be applied for organizing data related to several types of cancer. In particular, they draw connections between global epidemiology and selection of cancer cells within the organism. Their key hypothesis is that potentially cancer promoting mutations may be present at birth, but remain phenotypically insignificant until they encounter a selective environment. Increase in cancer incidence following migration and alterations of lifestyle may, thus, be explained by selection of existing mutations rather than induction of new ones.
Vineis and Berwick argue that ‘Carcinogenesis, at least for some types of cancer, can be interpreted as the consequence of selection of mutated cells similar to what, in the theory of evolution, occurs at the population level’. Taking a more conclusive stand, I will ague that carcinogenesis is an evolutionary process within the multicellular organism. Evolution by means of natural selection is a scientific principle that reaches far beyond the origin of the species6 and is applicable to all systems of inheritance, including somatic development. Genetic information is selected through the germline for its ability to build and control successfully reproducing organisms. Accordingly, evolution has favoured genes that assure growth control, coordinated action, and genetic stability. Once the germline genes enter into the somatic lineage, however, the rules are changed. Genetic (and epigenetic) information is selected for its ability to promote somatic proliferation. Consequently, there is a time-dependent breakdown of germline encoded control mechanisms, eventually leading to cancer (Figure 1).
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Much research has focused on identifying the initiating factor of carcinogenesis. There are several conflicting theories and apparently no simple answer.7 Is it a combination of random mutations, rise of genetic instability or self-sustaining aneuploidy? The evolutionary perspective redefines this problem and provides a very different solution. The somatic lineage departs from the germline a few days after conception and is subject to mutation and selection throughout the life of the organism. As emphasized by Vineis and Berwick, a mutation may be present from birth but remains insignificant until it encounters a selective environment. Pinpointing an initiating factor may, thus, be neither possible nor relevant. Carcinogenesis is evolution by means of natural selection in the somatic environment, and its origin resides in our multicellular constitution.
Vineis has previously introduced the term ‘selectogen’ to designate environmental factors that promote cancer by selection rather than mutation.8 This term draws attention to the evolutionary dimension of carcinogenesis. Unfortunately, it also confuses the issue. Selection and mutagenesis are two sides of the same coin. Different mutagens have different effects on different cells and organisms. All mutagens are therefore ‘selectogens’. The most intuitive assumption would be that mutagenic environments favour DNA control and repair mechanisms, but the relationship may be exactly the opposite. Mutagens paradoxically favour loss of DNA repair, and the underlying logic comprises the metaphor ‘don't stop for repairs in a war zone’.9 This logic is applicable to several of the examples presented by Vineis and Berwick, but as the authors maintain their categorical division between mutagens and ‘selectogens’, they fail to see the connection.
My major objection to this, and several related papers, concerns inconsistency regarding the unit of selection. Vineis and Berwick argue for ‘selection of mutated cells...at the population level’ and thereby indicate a model based on group selection theory. Later in the paper they refer to ‘selection of certain genotypes’, suggesting a gene-centred perspective to evolution. These differences in evolutionary perspective may seem as a trivial matter of semantics but have profound implications for the understanding of genetic instability. Vineis and Berwick draw attention to my recent review of this problem.10 Unfortunately, however, they have either missed or ignored my warning about cell selection models.
Evolution concerns propagation of heritable information through generations of cells—germline and somatic. Strictly speaking, it is this information that is selected, not the temporary constructs we recognize as cells. Selection implies that nucleotide sequences are conserved through generations. Sequences that are mutated are by definition not selected. The concept of cell selection is, thus, an approximation that deteriorates with increasing mutation rate. It collapses completely when it comes to modelling genetic instability, and selection of genetically unstable cells is a contradiction in terms. Carcinogenesis and other phenomena involving alteration of mutation rate, therefore, demands a molecular perspective to evolution.10
Despite this criticism, I believe Vineis and Berwick make an important contribution to the evolutionary understanding of carcinogenesis. The paper suggests unexplored relationships between germline polymorphisms, somatic mutations, and environmental factors. The challenge is to translate these examples and speculations into testable hypotheses and, thereby, broaden the interdisciplinary connection between molecular carcinogenesis, epidemiology, and Darwinian evolution.
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References |
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 Top References |
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1 Vineis P, Berwick M. The population dynamics of cancer: a Darwinian perspective. Int J Epidemiol 2006;35:1151–59.
2 Breivik J, Gaudernack G. Carcinogenesis and natural selection: a new perspective to the genetics and epigenetics of colorectal cancer. Adv Cancer Res 1999;76:187–212.[ISI][Medline]
3 Breivik J, Gaudernack G. Genomic instability, DNA methylation, and natural selection in colorectal carcinogenesis. Semin Cancer Biol 1999;9:245–54.[CrossRef][ISI][Medline]
4 Bardelli A, Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. Carcinogen-specific induction of genetic instability. Proc Natl Acad Sci USA 2001;98:5770–75.
5 Herzog CR, Bodon N, Pittman B et al. Carcinogen-specific targeting of chromosome 12 for loss of heterozygosity in mouse lung adenocarcinomas: implications for chromosome instability and tumor progression. Oncogene 2004;23:3033–39.[CrossRef][ISI][Medline]
6 Dennett DC. Darwin's dangerous idea—Evolution and the meaning of life. London: The Penguin Group, 1995.
7 Gibbs WW. Untangling the roots of cancer. Sci Am 2003;289:56–65.[ISI][Medline]
8 Vineis P. Cancer as an evolutionary process at the cell level: an epidemiological perspective. Carcinogenesis 2003;24:1–6.
9 Breivik J. Don't stop for repairs in a war zone: Darwinian evolution unites genes and environment in cancer development. Proc Natl Acad Sci USA 2001;98:5379–81.
10 Breivik J. The evolutionary origin of genetic instability in cancer development. Semin Cancer Biol 2005;15:51–60.[CrossRef][ISI][Medline]
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