Researchers at the Francis Crick Institute have shown that over 40% of variation in kidney cancer behaviour is due to non-genetic factors. These could be targeted by new treatments or help doctors understand the risk of a person’s cancer spreading.
Immunofluorescent images of TRACERx Renal tumour samples. Left shows tumour samples with low chromosome instability and right shows high chromosome instability. Magenta shows kidney cancer cells and yellow shows ENPP1 – which the cancer cells switch on to suppress the immune system.
Research into clear-cell renal cell carcinoma, the main type of kidney cancer, has mainly focused on genetic mutations in DNA that give the cancer an advantage.
But the impact of these mutations on tumour characteristics, such as how tumours interact with the body’s immune cells, is less clear. This is known as ‘transcriptional variation’ – how the genes are read and converted into proteins using a messenger molecule called RNA.
In research published today in Cancer Discovery, scientists at the Crick analysed the DNA and RNA of 243 samples from 79 people with kidney cancer in the TRACERx Renal study, to understand both genetic and transcriptional variation.
They showed that over 40% of transcriptional variation could not be accounted for by major cancer mutations in the DNA. Instead, it was happening when the DNA was being read in the cells and converted into proteins.
Their research identified four types of transcriptional variation which give tumours an advantage:
The researchers believe that understanding both genetic and transcriptomic variation is critical to identify new treatment targets. For example, their research suggests targeting the way tumours switch off cGAS-STING signalling would be beneficial.
The changes they observed in the tumour microenvironment also suggest that immunotherapies such as immune checkpoint inhibitors may work better if given earlier.
The next step for the team is to explore the clinical impact of these findings by validating the identified drug targets and biomarkers to improve treatment and prognosis for patients.
Samra Turajlic, Clinical Group Leader of the Cancer Dynamics Laboratory at the Crick, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, and Team Leader at The Institute of Cancer Research, London, said: “For many people diagnosed with kidney cancer, the tumours will spread to other parts of their body, making the disease much more difficult to treat. Understanding who is at risk of cancer spread and when to intervene is critical. By only looking at genetic changes in the tumour alone, we might be missing the entire context: what environment tumour cells are in and how their genes are being read to fuel unrestrained growth.”
Ángel Fernández Sanromán, Visiting Scientist at the Crick, PhD student at the Spanish National Cancer Research Centre (CNIO) and first author of the study, said: “We’ve taken a holistic investigation into kidney cancer to help bring together the many different factors that affect a person’s prognosis and importantly, identify new opportunities for intervention. For example, our results suggest that giving immunotherapy earlier is a promising future line of research, or that targeting a protein called ENPP1 could avoid immune suppression.”
Kidney cancer is one of the types of cancers currently investigated in the MANIFEST programme, where Samra and a national team of researchers are aiming to understand what other factors impact the chances of immunotherapy working.
