Abstract
Characterizing the mode—the way, manner or pattern—of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. Sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour. Here we propose that tumour architecture is key to explaining the variety of observed genetic patterns. We examine this hypothesis using spatially explicit population genetics models and demonstrate that, within biologically relevant parameter ranges, different spatial structures can generate four tumour evolutionary modes: rapid clonal expansion, progressive diversification, branching evolution and effectively almost neutral evolution. Quantitative indices for describing and classifying these evolutionary modes are presented. Using these indices, we show that our model predictions are consistent with empirical observations for cancer types with corresponding spatial structures. The manner of cell dispersal and the range of cell–cell interactions are found to be essential factors in accurately characterizing, forecasting and controlling tumour evolution.
Highlights
Atumour is a product of somatic evolution in which mutation, selection, genetic drift and cell dispersal generate a patchwork of cell subpopulations with varying degrees of aggressiveness and treatment sensitivity[1]
To test whether varying tumour architecture suffices to alter the tumour evolutionary mode, we considered four particular models with different spatial structures and manners of cell dispersal but identical evolutionary parameters
When simulating tumour growth in the absence of spatial constraints, rapid clonal expansions can result from driver mutations that increase the cell division rate by as little as a few percent, and the vast majority of cells eventually share the same set of driver mutations (Fig. 2a–d). These characteristics are reminiscent of chronic myeloid leukaemia, in which cell proliferation is driven by a single change to the genome[23], and acute myeloid leukaemia, which has relatively few drivers[24]
Summary
Atumour is a product of somatic evolution in which mutation, selection, genetic drift and cell dispersal generate a patchwork of cell subpopulations (clones) with varying degrees of aggressiveness and treatment sensitivity[1]. Factors proposed as contributing to tumour evolution include microenvironmental heterogeneity, niche construction and positive ecological interactions between clones[1,14,15,16,17]. Because such factors have not been well characterized across human cancer types, it remains unclear how they might relate to evolutionary modes. Because gene flow (the transfer of genetic information between localized populations20) is a principal force in evolutionary dynamics, we hypothesized that different tumour structures might result in different evolutionary modes. Whereas previous studies have assumed that tumours grow into empty space, our model allows us to simulate the invasion of normal tissue— a defining feature of malignancy
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