Researchers at the Francis Crick Institute and the UCL Cancer Institute have found that different cancers go through some of the same genetic aberrations at the same point in their evolution.
Chromosomal instability
A tumour’s genetic landscape changes over time. Chromosomal instability (CIN) is a form of genomic instability. It consists of dynamic changes in the number and structure of chromosomes. It is the result of the occurrence and tolerance of chromosome segregation errors during cell division. CIN is often linked to poor prognosis and results in somatic copy number alterations (SCNAs). SCNAs can act as substrates for selection and tumour evolution. However, the prevalence of CIN in late tumour evolution and the order of clonal and subclonal SCNAs, in relation to whole-genome doubling (WGD) events and metastatic dissemination, remains unclear.
In a paper, published in Nature, researchers in collaboration with the Max Delbrück Center for Molecular Medicine, developed a technique to analyse multiple samples from a single tumour to identify chromosomal changes in 1,421 samples from 394 tumours across 22 tumour types. The aim was to demonstrate that continuous chromosomal instability results in widespread SCNA heterogeneity.
Evolutionary events
The team observed parallel evolutionary events within separate subclones in 37% of tumours. In other words, they found that similar chromosomal changes took place in different subclones within tumours from the same patient. Interestingly, they also identified chromosomal changes that occurred across different tumour types at particular stages of cancer evolution. This included changes that impacted the tumours ability to evade the immune system or grow despite lack of oxygen.
Lead author and PhD student from the Cancer Evolution and Genome Instability Laboratory at the Crick, Thomas Watkins, stated:
“In a tumour there are lots of genetic changes taking place. The fact we saw similar chromosomal changes take hold independently within a tumour in separate subclones suggests these changes are important for the tumour and might lead to subclones with them ‘out-competing’ other subclones without them.”
Additionally, the team found that clonal and subclonal SCNAs tended to occur as ordered events, with certain events acting as catalysts for mutations. For example, WGD is a transformative event in tumour development. It is associated with late stage acquisition of clonal and subclonal SCNAs. The team believe that this so called ‘chaos’ could actually be something they could predict. This in turn could open the doors for new treatments.
The researchers are using their new technique on samples from lung cancer patients, as part of the CRUK’s TRACERx project. They hope that this will provide new insights into the genetic mechanisms that underpin the spread of lung cancer and allow tumours to evade the immune system.
Image credit: By Image Team – canva.com
