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Download (806Kb) City Research Online City, University of London Institutional Repository Citation: Noble, R. ORCID: 0000-0002-8057-4252, Kaltz, O. and Hochberg, M. E. (2015). Peto's paradox and human cancers. Philosophical Transactions of the Royal Society B: Biological Sciences, 370(1673), 20150104.. doi: 10.1098/rstb.2015.0104 This is the accepted version of the paper. This version of the publication may differ from the final published version. Permanent repository link: https://openaccess.city.ac.uk/id/eprint/24709/ Link to published version: http://dx.doi.org/10.1098/rstb.2015.0104 Copyright: City Research Online aims to make research outputs of City, University of London available to a wider audience. Copyright and Moral Rights remain with the author(s) and/or copyright holders. URLs from City Research Online may be freely distributed and linked to. Reuse: Copies of full items can be used for personal research or study, educational, or not-for-profit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. City Research Online: http://openaccess.city.ac.uk/ [email protected] Submitted to Phil. Trans. R. Soc. B - Issue Peto's paradox and human cancers Journal: Philosophical Transactions B For ReviewManuscript ID: RSTB-2015-0104.R1 Only Article Type: Research Date Submitted by the Author: 26-Apr-2015 Complete List of Authors: Noble, Robert; University of Montpellier II, Institute of Evolutionary Sciences Hochberg, Michael; University of Montpellier II, Institute of Evolutionary Sciences; Santa Fe Institute, Kaltz, Oliver; University of Montpellier II, Institute of Evolutionary Sciences Issue Code: Click <a href=http://rstb.royalsocietypublishing.org/site/misc/issue- PETO codes.xhtml target=_new>here</a> to find the code for your issue.: Subject: Evolution < BIOLOGY cancer, stem cells, carcinogenesis, Peto's Keywords: paradox, environment, disease http://mc.manuscriptcentral.com/issue-ptrsb Page 2 of 21 Submitted to Phil. Trans. R. Soc. B - Issue 1 2 3 4 5 6 7 8 9 10 11 Peto’s paradox and human cancers 12 13 Robert Noble1, Oliver Kaltz1, and Michael E Hochberg∗1,2 14 15 1Institut des Sciences de l’Evolution, Universit´eMontpellier II, 16 Place E Bataillon, 34095 Montpellier Cedex 5, France 17 2Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87501, 18 For ReviewUSA Only 19 20 21 22 23 Abstract 24 Peto’s paradox is the lack of the expected trend in cancer incidence 25 as a function of body size and lifespan across species. The leading hy- 26 pothesis to explain this pattern is natural selection for differential cancer 27 prevention in larger, longer-lived species. We evaluate whether a similar 28 effect exists within species, specifically humans. We begin by reanalyzing a recently published dataset to separate the effects of stem cell number 29 and replication rate, and show that each has an independent effect on 30 cancer incidence. When considering the lifetime number of stem cell di- 31 visions in an extended dataset, and removing cases associated with other 32 diseases or carcinogens, we find that lifetime cancer incidence per tissue 33 saturates at approximately 0.3-1.3% for the types considered. We fur- 34 ther demonstrate that grouping by anatomical site explains most of the 35 remaining variation. Our results indicate that cancer risk depends not only on number of stem cell divisions but varies enormously (∼10,000 36 times) depending on anatomical site. We conclude that variation in risk 37 of human cancer types is analogous to the paradoxical lack of variation in 38 cancer incidence among animal species, and may likewise be understood 39 as a result of evolution by natural selection. 40 Keywords. cancer, stem cells, carcinogenesis, Peto’s paradox, environ- 41 ment, disease 42 43 44 Introduction 45 All else being equal, the probability of obtaining at least a single invasive cancer 46 over an organism’s lifespan should scale with the number of “targets” – that is, 47 cell number, cell lifespan, and the number of cell divisions – over a lifetime. 48 Peto’s paradox is the lack of such a relationship [1], and is good evidence that 49 over the millions of generations of multicellular evolution, natural selection has 50 provided species with levels of cancer protection that are proportional to their 51 body masses and lifespans ([2, 3, 4]; Aktipis et al. [5], this issue). Several 52 articles in this Special Issue present background and new results on some of 53 the causes, protection mechanisms and emergent patterns. Far less studied is 54 ∗ 55 Corresponding author. Email: [email protected] 56 57 1 58 59 60 http://mc.manuscriptcentral.com/issue-ptrsb Submitted to Phil. Trans. R. Soc. B - Issue Page 3 of 21 1 2 3 4 5 6 7 the extent to which this phenomenon, is obtained within a species [6]. That 8 is, do different cell lineages within an organism show differing levels of cancer 9 protection based on their relative vulnerabilities (e.g., total stem cell number, 10 stem cell division rate, mutagenic exposure), and associated cancer mortality 11 risks for the whole organism? To the extent that cancer is a selective force 12 on differential resistance between cell lineages, such resistance, being a priori 13 costly to evolve, may also result in constraints on the evolution of body plans, 14 an aspect of Peto’s paradox that has rarely been investigated (Boddy et al. [7], 15 this issue; Kokko and Hochberg [8], this issue). 16 Here, we use the lens of evolution to reevaluate and reinterpret the data and 17 results of a recent study by Tomasetti and Vogelstein [9] (hereafter T&V), who 18 exploredFor possible sources Review of variation in risk between Only cancer types. We show 19 that c. 50% of variation in cancer risk is due to tissue size, indicating that, inde- 20 pendent of stem cell divisions, larger tissues are more likely to harbour cancers 21 than smaller tissues. A simpler measure of T&V’s Extra Cancer Risk (a classifi- 22 cation of cancers most likely to be caused by carcinogens) yields similar findings 23 to these authors, with some notable differences. Moreover, when using the total 24 number of stem cell divisions as a metric for cancers that are not typically the re- 25 sult of disease or carcinogenic exposure, and employing additional data sources, 26 we find that lifetime cancer incidence per tissue plateaus at approximately 0.3- 27 1.3% for the cases in an augmented dataset. We further demonstrate that most 28 of the remaining variation in cancer risk can be explained by grouping cancers by anatomical site (e.g., pancreas, bone, intestine), and that each site has a 29 very different risk per stem cell division. Our study indicates new directions 30 for research in showing how tissue characteristics may independently explain 31 variation in cancer incidence. We suggest that evolution by natural selection 32 has occurred on cancer prevention at different anatomical sites in humans as the 33 underlying driver of overall pattern, analogous to variation in cancer incidence 34 across species, i.e. Peto’s paradox. 35 36 37 Results 38 39 Tomasetti and Vogelstein [9] found a correlation between cancer incidence per 40 tissue and the lifetime number of stem cell divisions within the tissue for a set of 41 31 cancer types. They concluded that most of the variation in risk among cancer 42 types could be explained by random mutations and repair errors during cell 43 replication. Furthermore, the authors assessed the remaining variation in cancer 44 risk due to external environment and inherited factors, which they quantified with an Extra Risk Score (ERS). Cancers with high ERS are indeed known to 45 be associated with carcinogenic exposure (Fig. 2 in [9]). Below we reinterpret 46 their results through new statistical analyses and then reanalyse their dataset 47 with several new additions to assess signatures of natural selection for cancer 48 prevention. 49 50 51 Independent contributions of division rate and stem cell 52 number 53 Tomasetti and Vogelstein calculated the total lifetime number of stem cell divi- 54 sions (lscd) as s(2+d)−2, where s is the size of the organ’s stem cell population, 55 56 57 2 58 59 60 http://mc.manuscriptcentral.com/issue-ptrsb Page 4 of 21 Submitted to Phil. Trans. R. Soc. B - Issue 1 2 3 4 5 6 7 and d is the lifetime number of divisions per stem cell. They then tested for a 8 correlation between lscd and cancer incidence. One way in which their analy- 9 sis could be extended is to differentiate the individual contributions of s and d 10 to cancer risk [10, 11]. For instance, a small stem cell population with many 11 replications (e.g., esophageal cells) may have the same lscd as a large stem cell 12 population with few replications (e.g., lung cells, see Table S1 in [9]). How- 13 ever, in the former case, cancer risk may result mainly from replication errors, 14 while the latter has a considerably larger number of cells potentially exposed to 15 carcinogenic environments at any point in time. 16 We conducted a multiple regression analysis with cancer incidence as the 17 response variable, and log(d+1), log s, and the interaction of log(d+1) and log s 18 as the explanatoryFor variables. Review There was no significant Only correlation between the 19 two explanatory variables (r = 0.16,n = 31,p> 0.3), indicating that variation 20 in s is largely independent of variation in d.
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