Scientists have discovered that kidney cancer follows distinct evolutionary paths, enabling them to detect whether a tumor will be aggressive and revealing that the first seeds of kidney cancer are sown as early as childhood

The three Cancer Research UK funded studies, published in the journal Cell, shed light on the fundamental principles of cancer evolution and could lead to future clinical tests to give patients more accurate prognoses and personalized treatment.

In the first two papers, the TRACERx Renal team, analyzed over 1,000 tumor samples from 100 kidney cancer patients to reconstruct the sequence of genetic events that led to cancer in each patient.

The analysis reveals that there are three evolutionarily distinct types of kidney cancer. The first type follows a slow evolutionary path, never acquiring the ability to become aggressive.

The second type, by contrast, forms the most aggressive tumors, which evolve through a rapid burst of genomic damage – including changes that affect large chunks of the genome – early on in cancer's development. This gives a tumor all it needs to spread to many other parts of the body, often before the primary cancer is diagnosed.

The third tumor type acquires the ability to spread through a gradual accumulation of genomic damage. They typically spread over a longer period, often to just one site. These tumors are composed of many different populations of cancer cells, some of which are aggressive.

The researchers were able to confirm their findings by analyzing tumor samples obtained after death from patients in the post-mortem tumor sampling study, PEACE.

The researchers analyzed the traits that distinguish cells in a primary tumor that lead to secondary tumors, from those that never leave the primary tumor site. The cells that could spread were distinguished by changes at the chromosome level rather than mutations in genes. In particular, two specific chromosome changes that drive metastatic spread were found that could serve as a useful marker to identify patients that are at risk of metastatic disease.

The study's corresponding author Professor Charles Swanton said: "Understanding how cancers develop and evolve is likely to be critical in helping us piece together the information that will point the way to new treatment approaches and predict outcomes. 

In this study, we show that significant changes in the genome appear to be a particularly high-risk factor for early progression and death following surgery. We hope that in the future this work will help tailor the surgical and medical intervention to the right patients at the right time."

The third paper in this TRACERx Renal study analyzed the earliest events that trigger kidney cancer development. It shows they can take place in childhood or adolescence, up to 50 years before a primary tumor is diagnosed. The results present an opportunity for monitoring and early intervention in the treatment of kidney cancer, particularly in high-risk groups, such as those with an inherited risk of developing the disease.

"When Cancer Research UK scientists first revealed that the genetic makeup of cancers evolves, helping tumors to become resistant to treatments, we were faced with a monumental challenge of how to tackle this complexity. Now we know that there are rules in this complexity, and we could use these rules to help choose the best treatments, and potentially to diagnose some cancers much earlier."