Van Boxtel group
Cancer etiology.
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Professor Ruben van Boxtel
Why do certain individuals develop cancer and others do not? And why do children get cancer? Our vision is that by studying mutations in normal cells, we obtain insight into the etiology of cancer. We think this knowledge is crucial to improve cancer diagnostics and treatment, as welll as for developing preventive strategies.
On the origin of cancer: studying somatic evolution in normal tissues
Identifying the rate limiting steps of cancer initiation in human tissues is challenging as many factors can play a role. The mutations in the genomes of cells can serve as an archive of their life history. We aim to decode these archives in order to pinpoint the initiation of cancer and identify causal processes in human tissues. To study the etiology of cancer, we have 3 research themes in our lab.
“To beat cancer, we need to know how it starts.”
Ruben van Boxtel
Research group leader
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- Mutation accumulation in normal cells is required for the development of cancers.
Because aging is the biggest risk factor for cancer, it is thought that mutation accumulation is rate limiting for disease initiation. Indeed, as our cells age, they gradually accumulate mutations in their genomes. If a cell by chance acquires a bad mutation at the wrong time and place, malignant transformation can be triggered. According to this model, we should target these mutations, or their functional effects, in order to remove the driving force of the cancer and kill it.
However, with the recent developments of sequencing normal, noncancerous cells, we see that the mutation loads in normal tissues are already so high that it is very likely that there are always cells in our bodies with the right set of mutations, which are required for malignant transformation; yet we don’t have cancer. For example, in quite some newborns we can detect leukemia-driving fusion genes in their blood, yet these babies are perfectly healthy and do not develop leukemia. In addition, for certain cancer types, such as leukemia, young children show a higher incidence compared to young adolescents. This phenomenon represents an apparent paradox, as young cells should have less somatic (oncogenic) mutations than adult cells. It is very likely that mutation accumulation, although very necessary, is not the rate limiting step in cancer development.
Why then, do certain individuals develop cancer and others don’t? If mutation accumulation is not rate limiting for disease development, what is? And more importantly, shouldn’t we be targeting those rate limiting factors? In other words, if getting cancer is default, because of the relatively high mutation burden in normal tissues, how do our bodies keep the initiation of cancer in check and why does this sometimes fail?
Pinpointing the rate limiting steps in cancer initiation is challenging as many factors can play a role: ecological features within the various tissues, tissue damage responses, age, carcinogenic exposure, etc. Still, an increased understanding in how the body can keep cancer in check might revolutionize how we battle the disease: we have “stolen” our best ideas from nature, so why not this?
Research themes
To answer these questions, we have 3 research themes in our lab:
- Tissue-specific mutation accumulation in human stem cellsOrgan-specific cancer incidence varies significantly throughout the human body, which cannot be solely explained by different exposures to mutagenic environmental. Adult stem cells are likely the cellular targets for accumulation of pre-cancerous successive oncogenic hits, which eventually can give rise to tumor development, owing to their life-long capacity to propagate mutations to both self-renewing progeny and downstream progenitors. We aim to identify and study the mutational processes that are active in adult stem cells of various organs and precede oncogenic transformation.
- Tracking the origin of cancerDNA is the largest biomolecule in the cells, which unlike other biomolecules is irreplaceable. The processes causing mutations leave characteristic patterns in the DNA, which can serve as a functional readout of mutagenic and/or DNA repair activity.
- The etiology of therapy-related malignancies in cancer survivorsMost chemotherapeutic drugs act by fatally damaging the DNA or blocking the replication thereof. However, noncancerous cells are also damaged by treatment, which can result in the accumulation of DNA mutations in normal tissues with potentially adverse effects later in life, such as novel malignancies.
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