Modifiers of tumor development in Lynch syndrome

Lynch syndrome patients have an inactivating mutation in one of the genes involved in the DNA mismatch repair (MMR) system. MMR plays a crucial role in repairing errors in the DNA that occur during DNA replication before cell division. Colorectal cancer is often detected in Lynch syndrome patients before the age of 50, emphasizing the need for cancer prevention strategies in this patient group. Various factors influence the development of colorectal cancer. The research presented in this thesis focuses on identifying external and cell-intrinsic factors that impact colorectal cancer development in the context of Lynch syndrome. Understanding how these factors influence cancer development can help in the development of therapies to prevent or slow the onset of colorectal cancer. Chapter 1 provides an extensive overview of the current knowledge on Lynch syndrome, cancer prevention strategies, and factors that may influence the development of colorectal cancer. In Chapter 2, the study demonstrates that albendazole, a commonly prescribed medication for parasitic worm infections, not only inhibits cell division in worms but also affects cell division in the host. In the context of Lynch syndrome, albendazole might promote loss of the remaining functional MMR allele. Thus, the use of albendazole may pose a potential risk for Lynch syndrome patients. The intestine contains millions of bacteria, viruses, and single-celled organisms that together form the microbiota. A delicate balance exists between the intestinal lining, immune system cells, and the microbiota, where all components can influence each other. Chapters 3 and 4 describe the significant effect of altered microbiota composition on tumor incidence in the mouse model for Lynch syndrome. In Chapter 5, we focused on a cell-intrinsic factor that influences the MMR process and the likelihood of cancer development: the type of mutation found in a MMR gene. We studied a weak pathogenic mutation in MSH2, leading to only one amino acid change: the substitution of Valine at position 63 with Glutamic acid (V63E). This mutation was originally identified to be homozygously present in the germline of a very young patient with colorectal cancer. This research demonstrates how studying mutations from patients can provide fundamental insights into the MMR process. Chapter 6 focuses on cancer prevention strategies. One approach is to remove MMR-deficient cells from the intestinal epithelium before they transform into cancerous cells. Unfortunately, no substances were identified that were selectively toxic to non-transformed MMR-deficient cells without affecting MMR-proficient cells.. The findings in this chapter suggest that chemoprevention, as a therapy to remove MMR-deficient cells from the intestinal epithelium, may not yet be a viable treatment option. Finally, in Chapter 7, the implications of the findings from this dissertation are discussed for further research on the influences of external factors on colorectal cancer development in the context of Lynch syndrome, with an emphasis on the influence of the microbiota and important open questions in this research field. The current state of cancer prevention strategies is also discussed, along with considerations for future research to minimize the development of colorectal cancer in Lynch syndrome patients.