Ruben van Boxtel Group
Cancer Etiology, Mutagenesis and Clonal Evolution
Why do we develop cancer and how does genotoxic treatment cause late adverse effects in survivors? Although these questions seem distinct, they are in fact interrelated. Exposure to environmental genotoxic stress, such as UV-light and tobacco smoke can cause cancer. Similarly, exposure to radio- and chemotherapy increases the risk for a therapy-related second malignancy in cancer survivors. In fact, second malignancies are one of the major causes for long-term mortality in childhood cancer survivors. However, not all exposed individuals will get cancer. Genotoxic exposure causes an elevated mutation burden in the DNA of our cells, which increases the chance of acquiring oncogenic hits needed for malignant transformation. Adult stem cells are the most likely cellular targets for sequential accumulation of these oncogenic hits, because of their longevity and ability to propagate mutations to progeny. In addition, adult stem cells play a crucial role in regenerating damaged tissues in cancer patients.
Why then, do some individuals develop cancer and others do not? Cancers are formed by evolutionary processes acting in normal tissues. Stochastically acquired genetic alterations cause phenotypic diversity and evolutionary forces, such as selection and drift, subsequently shape clonal dynamics within cell populations. Although both necessary, it is unclear which of these (i.e., phenotypic diversity and context-dependent selection) is rate-limiting for cancer development. To determine which of these factors is rate-limiting, mutation accumulation in adult stem cells and clonal dynamics in human tissues must be characterized. However, cataloguing somatic mutations in human stem cells is technically challenging due to the polyclonal nature of healthy tissues and the high error rate of single cell sequencing techniques. We have pioneered the development of experimental and bioinformatic approaches to catalogue and characterize genome-wide mutation accumulation in normal human stem cells. By studying genomes of adult stem cells in human tissues at risk for cancer, we envision to identify which evolutionary factors are rate-limiting for carcinogenesis. Our vision is that this knowledge will improve diagnostics and enable the development of novel strategies for targeting and perhaps even preventing carcinogenesis.