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Actionable metastatic cancer genomes remain stable over time

A new study, published in Nature Medicine, has found that driver mutations in metastatic cancer genomes remain stable over time. The findings have the potential to change how cancer treatments are approached.

Analysing cancer genomes

Analyses of somatic mutations in cancer genomes have hugely improved our understanding of the molecular events that drive malignancies. The identification of mutations has led to many therapies that specifically target those genomic alterations.

However, current cancer drugs are becoming increasingly specific, targeting DNA alterations within a distinct tumour cell. Due to this, the target mutations of these cancer drugs are only present in small subgroups of patients. This is contributing to a growing concern that many cancer patients will not benefit from these new treatments.

Whole genome sequencing uncovers multiple mutations

A solution to this problem is to analyse the entire tumour genome, rather than single cells. This is known as whole genome sequencing (WGS) and is a comprehensive profiling technique, which allows for the identification of multiple mutations at once.

WGS is currently only carried out to a limited extent in cancer treatments, due to high costs. Moreover, the frequency with which WGS should be repeated is uncertain, as it is unknown how much the tumour genome evolves over time. To investigate this, the researchers of this study analysed WGS and clinical data of 231 patients with a variety of metastatic solid tumours.

Analysing biopsy pairs

In total, the study analysed the WGS of 250 biopsy pairs that were longitudinally collected over the treatment course of the patients.

First, the scientists investigated how many genomic alterations occurred in the time between the two biopsies. It was found that the number of mutations significantly increased in the interval, making the genome more complex. Despite this, it was found that the proportion of cancer cells in tumour tissues was not significantly different between the first and second biopsies. This suggests that the accumulated mutations were passenger mutations, rather than driver mutations. As the name suggests, driver mutations drive cancer progression. Passenger mutations, on the other hand, are seemingly random mutations that do not directly drive disease.

Evolution of cancer genomes

Next, the evolution of driver mutations was analysed. Overall, the number of driver mutations per sample did not significantly increase over time. In addition, no individual gene was significantly associated with an increased frequency of driver gains. However, the longer the time between the two biopsies was, the higher the likelihood that the second biopsy gained new drivers.   

Following this, researchers sought out how frequently the second WGS analyses identified treatment targets that were not found in the first biopsy. The answer was not often at all! In 91% of patients, the first WGS analysis already provided a complete view of the investigational treatment opportunities. This suggests that the evolution of the actionable cancer genome is limited.

Future implications

Overall, the results show that although the metastatic cancer genome became increasingly complex between biopsies, the number of functional driver mutations remained constant. This indicates that the actionable metastatic cancer genome is remarkably stable over time. Therefore, for the vast majority of patients, a single WGS analysis is sufficient to identify personalised treatment opportunities.

As well as increasing the cost-effectiveness of utilising WGS in the clinical setting, these findings show that WGS is effective early on in the course of metastatic disease. This has the potential to greatly improve the way treatment of metastatic cancer is approached. However, before this can happen, further studies will be required to validate WGS for clinical use. Moreover, this study was done over a limited time span and did not examine primary tumours. Therefore, these avenues should be explored further in future work.

Photo by National Cancer Institute on Unsplash

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Cancer / Mutations / Sequencing

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