Catch my drift? Making sense of genomic intra-tumour heterogeneity

Abstract

The cancer genome is shaped by three components of the evolutionary process: mutation, selection and drift. While many studies have focused on the first two components, the role of drift in cancer evolution has received little attention. Drift occurs when all individuals in the population have the same likelihood of producing surviving offspring, and so by definition a drifting population is one that is evolving neutrally. Here we focus on how neutral evolution is manifested in the cancer genome. We discuss how neutral passenger mutations provide a magnifying glass that reveals the evolutionary dynamics underpinning cancer development, and outline how statistical inference can be used to quantify these dynamics from sequencing data. We argue that only after we understand the impact of neutral drift on the genome can we begin to make full sense of clonal selection. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer? Edited by Dr. Robert A. Gatenby.

Keywords: Clonal evolution of cancer; Clones; Intra-tumour heterogeneity; Neutral evolution; Next generation sequencing; Selection.

Fig. 1

The dynamics of somatic evolution. Somatic evolution is the result of the interplay of three fundamental forces: random mutation, random drift, non-random selection. Random mutations are inherently stochastic, but can be handled with existing mathematical tools such as Poisson statistics. Drift is also stochastic, and can be modelled with random sampling. Selection instead is non-random, but comprehensive mathematical tools to describe the result of selection are still lacking. When selection is not in operation, only the first two processes act, and the combination of random mutation and random drift together are what is defined as neutral evolution.

Fig. 2

The fractal pattern of neutral evolution. In the absence of selection, genotypes are free to mutate as the tumour grows, generating a well-defined fractal pattern in the phylogenetic history of the malignancy, with more and more rare mutations (rare branches) at lower and lower frequencies. This pattern is characterised by a 1/f distribution of the allele frequencies of mutations within a population.

Fig. 3

Neutral evolution versus selection. When neutral dynamic are operating, new mutations in the genome represent just labels for individual cell lineages and so the frequency of new mutations decreases at a rate inversely to tumour size (this 1/f pattern of allele frequencies is characteristic of neutral growth). In the case of selection instead, both subclonal driver and passenger mutations are carried at higher frequency than expected under neutrality, generating signatures of clonal outgrowth (‘too many’ mutations at high frequency) that distinguishes the pattern of allele frequencies under selection from the neutral case. Generation time goes from left to right, starting from a single cell that expands exponentially.

Fig. 4

Spatial properties of growing clones. When tumours grow in a disordered fashion, when cell push each other around by means of proliferation pressure, characteristic patterns of subclonal intermixing are spontaneously generated. In this simulated case, a new mutation in red originated early during the growth of the tumour, but was scattered by the disordered growth dynamics, and propagated to far away locations in the malignancy by the growth of the neoplasm. This occurs just by means of disordered growth, with no active migration of cells and it is an indication of a potentially invasive phenotype.