Hereditary cancer genetics: germline variants of DNA repair genes and the consequences for carcinogenesis

Hereditary cancer syndromes account for 5-10% of all cancer cases. Identifying and understanding hereditary forms of cancer is crucial for developing effective treatment and surveillance strategies.<br>This dissertation focuses on Lynch syndrome, one of the most common hereditary cancer syndromes. Through tumor studies, we have demonstrated biological differences between colorectal tumors in different groups of Lynch syndrome patients. These differences involve the DNA of tumor cells and the immune responses triggered by them. They are associated with clinical variations, such as colorectal cancer risk, and may contribute to the development of subgroup-specific treatment and surveillance guidelines. Additionally, this dissertation explores factors contributing to colorectal cancer development in Lynch syndrome patients undergoing regular colonoscopies—procedures intended to detect and remove (pre-)cancerous lesions. This includes alternative or accelerated tumor development pathways that are harder to detect during colonoscopy, as well as colonoscopy-related factors such as procedure quality. Finally, this dissertation extends its focus to lesser-known hereditary cancer syndromes beyond Lynch syndrome. It discusses potential associations between variants in three relatively new genes—MCM8, MCM9, and HROB—and infertility, colorectal polyps, and different types of cancer. This underscores the need for further research on these genes and their inclusion in (diagnostic) screening panels.<br>