Cancer in the light of evolution – from cancer genomes towards novel treatment and prevention approaches

Abstract

Cancer is one of the deadliest diseases and a major health burden for mankind. In the past, our conceptual understanding of cancer has largely been determined by the medical need to classify distinct stages of the disease to select the most appropriate therapy. This view created only a very limited understanding of the true processes governing the disease, as it only perceives a snapshot at the time point of operation or the initial therapy. Cancer, though, is the result of a long-lasting evolutionary process following exponential expansion rules. It usually takes years or even decades until an initially hidden transformed cell in one of our organs is being noticed through symptoms as a clinically detectable lesion. During this time of inapparency, multiple genomic alterations accumulate from generation to generation of replicating cells, that are all governed by the nature of the initial molecular hit that was responsible to push normal somatic cell into the state of a true cancer precursor. To develop better tools to diagnose, treat and prevent cancer, it becomes more and more clear that is essential to understand the dynamic genomic processes that allow pre-cancer cells to expand and continuously change their biological behavior. Recent advances in DNA sequencing techniques allowed to obtain an unprecedented amount of high-resolution data on genomic changes in cancer cells. This increasing knowledge helps to reconstruct the genomic history of individual cancer cells. However, it also indicates that pre-cancerous lesions in all of us seem to be substantially more common than previously anticipated, suggesting that we are well armed with a broad range of genetic and immunological weapons to control or defeat the vast majority of initial cancer cells clones. We will discuss the current understanding of these evolutionary processes using the paradigmatic example of DNA mismatch repair-deficient, microsatellite-unstable cancer. We will outline how a better understanding of cancer evolution can guide the development of tailored tumor diagnostics and treatments and retain the clues to effective cancer prevention.