Cancer cells often develop in a pattern according to an established set of rules that researchers have now identified.
A tumour is not just a tumour.
Over time, a tumour develops and accumulates more and more genetic mutations, enabling it to accelerate its growth.
The way a tumour progresses from a few mutations in a few cells to spreading throughout the body and being extremely complex in composition may seem completely arbitrary.
However, this is not the case according to new research published in Nature.
The research reveals how the genome of a tumour can be remodelled in an ordered fashion in a person with cancer .
“We know that people with cancers with more diverse genetic mutations within tumours have worse outcomes, and we wanted to determine whether the acquisition of these mutations is completely arbitrary or whether they occur according to a pattern that can be identified and perhaps be used to better understand and treat the people with cancer,” explains Emilia L. Lim, postdoctoral fellow, Francis Crick Institute, London, United Kingdom.
Tumour genomes evolve throughout tumour development
The researchers from the Francis Crick Institute and the Max Delbrück Center for Molecular Medicine in Germany developed a technique to analyse the genetic composition of several samples in the same tumour.
The researchers used this technique to identify changes in the genomes of 1,421 cancer samples from 394 patients across 22 types of tumours. The researchers examined multiple regions of each tumour to determine the extent of mutation across individual tumours. Importantly, the researchers categorized the mutations within tumours according to whether they occurred early or late in tumour development.
The study yielded several interesting results.
The researchers found that the genome is continually remodelled as a tumour develops.
“One might assume that some tumour genomes remain the same throughout tumour development, but that is not what we found. Instead, a tumour genome continually acquires mutations as it matures, which enables it to persist,” says Emilia L. Lim.
The group leader behind the study, Charles Swanton, Professor at the Francis Crick Institute, explains: “The presence of similar changes in the genome over time supports the assumption that a tumour must pass through a certain number of genetic pathways as it develops. Identifying these pathways might bring us closer to being able to write the evolutionary rulebook of cancer.”
Cancer develops through the same stages every time
When the researchers examined when the genetic changes occurred in the tumours, they found that for each cancer type the genome was remodelled at distinct chromosomal locations at early, intermediate and late stages of tumour development.
The researchers further discovered that the genome remodelling appeared to follow some rules that caused the same mutations to occur independently in different parts of a tumour, suggesting that these specific mutations were important and thus occurred repeatedly in the development of the tumour. The researchers saw this parallel development in as many as 37% of tumours.
“Many genetic changes occur in a tumour. The fact that we saw similar genetic changes take root independently in the same tumour, but in different regions, indicates that these changes are important for the tumour and may lead to subclones with these mutations outcompeting subclones without these mutations,” says co-author Thomas Watkins, PhD student, Francis Crick Institute.
The researchers also found the same mutations in different types of cancer. This suggests that some specific mutations accelerate tumour growth across types of cancer: for example, because they help the cancer cells to evade the immune system or enable them to grow even in the absence of oxygen.
Doubling the genome enables the acquisition of more mutations
Further studies of the data showed that tumours appear to use specific mutations to achieve certain traits in early or late development.
For example, the researchers found that tumours often double the amount of genetic material in the cancer cells through whole-genome doubling.
By doubling the genome, tumours increase the amount of genetic material that can be modified when they need to evade the immune system and find ways to invade new tissues.
The research showed that genome doubling is often followed by the acquisition of many mutations.
“This doubling of the genome may actually catalyse the accumulation of more genomic alterations,” says Emilia L. Lim.
Improving treatment strategies
According to Emilia L. Lim, the study advances researchers’ knowledge on how a tumour develops and what steps it has to go through to spread to other parts of the body.
In the future, this knowledge may be used to predict the pattern of tumour development and aid in clinical decision making.
“Our goal is to create a rulebook of tumour evolution that enables us to forecast the development of a tumour, what it is likely to do next and how we can prevent this from happening. In future, we hope to determine, based on the early events in tumour development, where a tumour is heading. This information may be very important, for example, for clinicians who need to determine how they can best treat an individual patient,” says Emilia L. Lim.
“Pervasive chromosomal instability and karyotype order in tumour evolution” has been published in Nature. The Novo Nordisk Foundation has awarded a grant to Emilia L. Lim.