As part of the Pan-Cancer Analysis of Whole Genomes Consortium, researchers analysed the whole genomes of tumour samples from over 2,600 patients. Here, the team identified a high prevalence of intra-tumour heterogeneity.
As cancers evolve, they accumulate somatic mutations. Some of these mutations are drivers that confer fitness advantages to the cells. This leads to clonal expansion. Intra-tumour heterogeneity (ITH) is the result of late clonal expansions, spatial segregation and incomplete selective sweeps that lead to genetically distinct cellular populations. While clonal mutations are shared by all cancer cells, subclonal mutations are only present within a subset.
ITH is a key clinical challenge. It provides genetic variations that not only drive cancer progression but can also lead to the emergence of drug resistance. ITH can be used to predict progression and prognosis of disease. For example, ITH at the level of copy number alterations associates with increased risk of relapse in several cancers, including non-small cell lung cancer. To date, ITH remains poorly characterised across cancer types. There is also substantial uncertainty surrounding the selective pressures operating subclonal populations.
In this paper, published in Cell, researchers analysed the whole genomes of 2,658 cancer samples, spanning 38 cancer types. They found that 95.1% of samples contained at least one identifiable subclone.
The team also observed that the levels and types of genetic changes between cancer types varied. Even within the same tumour, researchers found that the genetic architecture was widely different between subclones. They suspect that these subclones arose due to specific evolutionary pressures. These pressures can occur at different times during tumour development or within different tumour areas. This theory was supported by evidence that found that the evolution of subclones was affected by whether the genetic changes were advantageous or not. In other words, subclones with more advantageous genetic changes were more likely to develop.
Peter Van Loo, study author and group leader of the Cancer Genomics Laboratory at the Crick stated:
“Cancers are constantly changing over time, so it’s important to recognise that a sample taken from a tumour reflects a single point in time and the cancer will continue to evolve after this. They can grow into a patchwork with sections driven by different mutations and evolutionary pressures.
Understanding more about the evolution of subclones, why they develop in one direction over another, as well as how common they are, could help doctors better predict the levels of and types of variation likely to be present in a specific cancer type.”
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