By: Victoria Forster
Scientists studying kidney cancer have found that the first DNA damage eventually leading to cancer can occur as early as childhood, in some cases fifty years before diagnosis.
In a trio of studies simultaneously published on Thursday in the journal Cell, researchers have provided vital new information as to how kidney cancer begins, evolves and progresses, which they hope will lead to better tests to detect the cancer early and more personalized treatment options for patients.
One of the research papers, co-led by researchers at the Sanger Institute in Cambridge, UK showed that the genetic abnormalities that eventually lead to cancer can occur decades before the primary tumor is diagnosed.
Dr Peter Campbell, one of the leaders of the study said: “What is remarkable is that the hallmark genomic event that characterises kidney cancer takes place on average 40 to 50 years before the cancer is diagnosed.”
In kidney cancer, this event is frequently a loss or a gain of a part of a large chunk of DNA called a chromosome. In this case both happen simultaneously, paving the way for further genetic events which further destabilize the cell, leading it further down the road to becoming cancerous. Abnormal numbers of chromosomes are frequently found in cancer, but by identifying that this specific abnormality typically occurs so long before diagnosis, the researchers hope that their results will open up new opportunities for monitoring and early detection and treatment of kidney cancer. This may be especially useful for people who have a high-risk of developing the disease, such as those with close family members who have been affected.
“These first seeds are sown in childhood or adolescence – knowing the sequence of events and their timings opens opportunities for early intervention,” said Campbell.
Kidney cancer is the 7th most commonly diagnosed cancer, affecting over 60,000 Americans annually, with cases increasing in the developed world. Researchers have previously been puzzled as to why patients with seemingly very similar kidney tumors experience such vastly different outcomes, with some dying quickly but some surviving for decades after treatment, but the new research provides vital clues as to why this occurs.
In the other papers published, the scientists showed that although cancerous kidney tumors follow three distinct pathways of evolution and they suggest that knowing which of these has happened in each individual kidney cancer patient could lead to more accurate prognoses and personalized treatment.
Lead author of the study, Dr Samra Turajlic, Consultant oncologist and Clinician scientist at the Francis Crick Institute, London said: “The outcomes of patients diagnosed with kidney cancer vary a great deal – we show for the first time that these differences are rooted in the distinct way that their cancers evolve.”
The teams based at the Francis Crick Institute at University College London and at London hospitals analysed over 1,000 tumor samples from 100 kidney cancer patients to figure out the sequence of genetic alterations which eventually led to cancer in each patient.
The first tumor type is slow to evolve and never becomes very aggressive, the second, experienced by around a third of patients is the most aggressive, with tumors acquiring a lot of genetic damage very quickly, leading to tumors which have often spread to other parts of the body before diagnosis and hence are particularly difficult to treat. The third type is somewhat a mixed bag, with some aggressive cells and some not-so aggressive cells and has the ability to spread via a slow and steady accumulation of genetic errors, taking a long time to spread and typically to just one other site in the body.
Studying the evolution of cancers is not new and it is widely accepted that cancers develop over time, acquiring more and more DNA mutations until they reach a critical point at which the cell finally becomes cancerous. For some cancers, such as many childhood cancers, the number of mutations needed to push a cell over this limit is very low, but some cancers can have thousands of mutations.
“Knowing the next step in cancer’s evolutionary trajectory could tailor the treatment choice for individual patients. Patients with the least aggressive tumors could be spared surgery and monitored instead and those with gradually evolving tumors could have the primary tumor surgically removed even after it has spread,” said Turajlic.
The accumulation of DNA damage can even start before birth, for example the first DNA mutations eventually leading to childhood leukemia are thought to occur while the fetus is still in the womb. Scientists have been able to look back at normal blood samples taken at birth from children that later went on to develop leukemia, and detect tiny amounts of the same damaged DNA that was found sometimes over a decade later in the leukemia cells of these children. In that decade, this initial DNA mutation had been joined by others that eventually resulted in the blood cells turning cancerous.
However when the leukemia researchers studied healthy children, they also found this damaged DNA in the blood samples at birth, but only one in a hundred of these children went on to actually develop leukemia. Whether every person with these early genetic events for kidney cancer actually goes onto develop kidney cancer is currently unknown and further research addressing this is important to decide how this information should be used.
For example, screening people for cancer-predisposing mutations which arise several decades before the cancer actually develops is an excellent idea in principle, but currently difficult to justify, especially considering the cells with mutations may only be present in a tiny area of the kidney. Liquid biopsies may be able to address these issues, but they probably aren’t reliable enough yet and much more work is needed to decide what to do next to ultimately benefit patients. Is early detection the overall goal, or even prevention of these cancers entirely?