Born to be bad: researchers identify the genetic roots of ‘killer’ kidney cancers

In a landmark genetics study, a multi-institutional group of researchers have uncovered three distinct evolutionary paths for kidney cancer, allowing them to determine whether a tumor will be aggressive. The findings were recently published in Cell.

The findings arose from three studies. In the first two papers, the researchers analyzed more than 1000 tumor samples from 100 clear cell renal cell carcinoma patients in order to reconstruct the sequence of genetic events that led to the cancer in each patient.

From this analysis they identified three types of kidney cancer. The first followed a slow evolutionary path and never acquired the ability to become aggressive whereas the second type evolved through a swift burst of genomic damage, by which the most aggressive tumors are formed.

The burst of genomic damage involved changes in large portions of the genome early on in the cancer’s development, enabling the tumor to metastasize before the primary cancer is diagnosed.

The third type of tumor acquires the ability to metastasize, over a long period of time and often to one site, through a progressive accumulation of genomic damage.

Sir Harpal Kumar (Cancer Research UK), explained: “For years, we’ve grappled with why patients with seemingly very similar diagnoses have such vastly different outcomes – some dying very quickly and some surviving for decades after treatment. These ground-breaking studies help us unravel this conundrum.”

To confirm their findings, the team analyzed tumor samples obtained after death from patients in a post-mortem tumor sampling study, termed PEACE.

Additionally, the team analyzed the traits that distinguish cells in the primary tumor that lead to secondary tumors, from those that never leave the primary tumor site. They discovered two specific chromosome changes that drive metastatic spread, which could serve as useful markers for identifying patient at risk of metastatic disease.

The third paper in this study uncovered the earliest events that trigger kidney cancer development, highlighting that changes can take place up to 50 years before the primary tumor is diagnosed.

“We can now say what the initiating genetic changes are in kidney cancer, and when they happen. What is remarkable is that the hallmark genomic event that characterizes kidney cancer takes place on average 40–50 years before the cancer is diagnosed,” corresponding author, Peter Campbell, from the Wellcome Sanger Institute (UK), commented.

“These first seeds are sown in childhood or adolescence – knowing the sequence of events and their timings opens opportunities for early intervention,” Campbell added.

“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. Knowing the next step in cancer’s evolutionary trajectory could tailor the treatment choice for individual patients in the next decade,” concluded lead author Samra Turajlic from the Francis Crick Institute and The Royal Marsden (both London, UK).

Source: Mitchell TJ, Turajlic S, Rowan A et al. Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal Cell doi:10.1016/j.cell.2018.02.020 (2018) (Epub ahead of print);  Turajlic S Xu H, Litchfield K et al. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal Cell doi:10.1016/j.cell.2018.03.043 (2018)(Epub ahead of print); Turajlic S Xu H, Litchfield K et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal doi:10.1016/j.cell.2018.03.057 (2018)(Epub ahead of print);www.crick.ac.uk/news/science-news/2018/04/12/killer-kidney-cancers-identified-by-studying-their-evolution/