Mapping mutations in human cells: How extrinsic agents and aging alter the genetic code

Abstract

During life, the DNA of our cells is constantly damaged by various exposures. These exposures can be both cell-intrinsic, or originate outside the body, such as sunlight or chemotherapy. DNA-damage in a healthy cell can result in mutations, which can lead to cancer. For the prevention of cancer, it is crucial to understand how mutations in healthy cells are induced. In this thesis, we describe the mutations present in healthy blood stem cells, and we aim to explain how these are induced. In each healthy blood stem cell in our body, mutations accumulate with a rate of 14 mutations/year, with little difference between blood cancer in both number and type of mutations. During chemotherapy treatment the number of mutations dramatically increases, which may explain the increased risk for cancer after chemotherapy treatment. In addition, this thesis describes how specific bacterial strains can induce mutations. These pks+ E. coli bacteria produce a toxin named colibactin, which can induce DNA damage. After injection of these bacteria in mini-guts, we can observe mutations at specific DNA positions in exposed cells. These positions clearly indicate how colibactin binds to the DNA. Furthermore, we can detect the same recognizable mutations in the genomes of colorectal cancers, which means that these bacteria have mutated in the ancestral cell of the colorectal cancers in the past. This knowledge on how bacteria and chemotherapy can induce mutations can be used to better understand the origin of cancer and may in eventually contribute to the prevention of cancer.