Evolution of the cancer genome

Abstract

Human tumors result from an evolutionary process operating on somatic cells within tissues, whereby natural selection operates on the phenotypic variability generated by the accumulation of genetic, genomic and epigenetic alterations. This somatic evolution leads to adaptations such as increased proliferative, angiogenic, and invasive phenotypes. In this review we outline how cancer genomes are beginning to be investigated from an evolutionary perspective. We describe recent progress in the cataloging of somatic genetic and genomic alterations, and investigate the contributions of germline as well as epigenetic factors to cancer genome evolution. Finally, we outline the challenges facing researchers who investigate the processes driving the evolution of the cancer genome.

Figure 1

Natural selection acting at the organismal and somatic levels. Multiple selective pressures are present at both the organismal (a) and somatic (b) levels. In the organismal realm, competition with other species, predation, resource limitation and others dictate the habitat boundaries and frequencies of organisms. In the somatic realm, constant immune system surveillance for abnormality, targeted therapy to inhibit division of particular cells, the constraints of the cell cycle program, the blood supply for nutrients, and many other factors determine the microenvironment within which each cell exists. Any cell that gains the capability to overcome these physiological constraints and to avoid immune system attack gains a reproductive advantage over its neighbors, thus leading to clonal expansion. An analogy in the organismal world to such clonal expansion is a growing herd of zebras that out-competes other grazers and successfully evades predators. An important distinction between organismal and somatic evolution is that adaptive traits are inherited via sexual and asexual reproduction, respectively.

Figure 2

Cancer progression. The progression to cancer begins with the emergence of the first genetic, epigenetic or genomic alteration in normal cells (blue circles) and usually ends with a large population of malignant cells invading multiple tissues (a). This process involves the evolution of multiple ‘novel’ cellular traits. Most somatic alterations in epithelial cells lining the colon, for instance, are not advantageous and will disappear with the death of a cell. Occasionally, an alteration that increases the proliferation rate of a cell arises, allowing this cell to increase in number. This population of ‘rogue’ cells can decline with the onset of anti-cancer therapy; however, the arrival of an alteration conferring drug resistance reverses the effects of treatment and allows new growth (b). In some cases, resistance to an anti-cancer drug may already be present in a small subset of tumor cells. In such a scenario, the population of sensitive cancer cells will decline and eventually be replaced by drug-resistant cells. Further alterations may be necessary to enable tumor cells to metastasize (c) and spread to other tissues (d); these changes might arise before diagnosis and treatment or, as shown in this example, thereafter.

Figure 3

Genetic and epigenetic determinants of cancer genome evolution. The human genome is organized into highly complex structures with multiple levels of organization. The highest level comprises chromosome packaging into the cell nucleus (a). DNA strands in close spatial proximity are more likely to interact during replication and transcription, leading to chromosomal rearrangements and gene fusions (b). Aberrant methylation and acetylation of histone tails can result in gene expression and splicing variation (c). DNA sequence alterations may modulate gene expression and change protein amino acid composition (d). Aberrations at all of these levels may influence the mutational landscape of cancer genomes.