Spatial structure increases the waiting time for cancer

TY - JOUR

T1 - Spatial structure increases the waiting time for cancer

AU - Martens, Erik Andreas

AU - Kostadinov, Rumen

AU - Maley, Carlo C

AU - Hallatschek, Oskar

PY - 2011/11

Y1 - 2011/11

N2 - Cancer results from a sequence of genetic and epigenetic changes that lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells and thus to a selective advantage of precancerous cells. The notion of cancer progression as an evolutionary process has been attracting increasing interest in recent years. A great deal of effort has been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a wellmixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones and decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale L c. These characteristic features of clonal interference may help us to predict the onset of cancers with pronounced spatial structure and to interpret spatially sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer and possibly other cancers where spatial structure matters.

AB - Cancer results from a sequence of genetic and epigenetic changes that lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells and thus to a selective advantage of precancerous cells. The notion of cancer progression as an evolutionary process has been attracting increasing interest in recent years. A great deal of effort has been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a wellmixed cell population, even though pre-cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones and decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale L c. These characteristic features of clonal interference may help us to predict the onset of cancers with pronounced spatial structure and to interpret spatially sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer and possibly other cancers where spatial structure matters.

KW - Cancer,Spatial structure,Waiting time,clonal expansion

U2 - 10.1088/1367-2630/13/11/115014

DO - 10.1088/1367-2630/13/11/115014

M3 - Journal article

SN - 1367-2630

VL - 13

SP - 115014

JO - New Journal of Physics

JF - New Journal of Physics

ER -