Exploring the genetics of hereditary cancer, with a focus on colorectal cancer

Abstract

Hereditary cancer syndromes are characterized by an inherited genetic predisposition that increases an individual's risk of developing specific types of cancer. Hereditary cancer accounts for about 5-10 % of all cancer cases, and most hereditary cancer syndromes follow an autosomal dominant inheritance pattern. The genetic mecha-nisms underlying predisposition to hereditary cancer syndromes include errors in tu-mor suppressor genes, DNA repair genes, oncogenes and other genes involved in cellu-lar processes. This thesis aimed to enhance diagnostic yield and advance understanding of the ge-netics underlying hereditary cancer syndromes, with a specific focus on hereditary colorectal cancer, through the application of novel technologies and AI-integrated analysis. Applying next-generation sequencing and broad gene panels led to the identification of pathogenic variants in novel genes, POLE and GREM1, which now are established as high risk genes for hereditary colorectal cancer. We also found that bi-allelic non-sense variants in MLH3 give rise to colorectal cancer. The investigation of genotype-phenotype relationships across different types of hereditary cancer syndromes re-vealed overlapping manifestations between syndromes, suggesting broader gene pan-els in clinical diagnostics. Families with a pattern of hereditary colorectal cancer sur-prisingly harbored pathogenic variants in genes BRCA1 and RAD51C, primarily asso-ciated with hereditary breast- and ovarian cancer. Additionally, we quantified the transcript level from promoter 1B of the APC gene. Significantly lower expression levels were observed in patients with sporadic colorectal cancer compared to healthy individuals. In conclusion, combining advanced sequencing with AI-driven analysis improves the handling of large genomic datasets, enhancing detection, classification, and interpre-tation of variants in hereditary cancer syndromes. In addition, the transcript level generated from promoter 1B of the APC gene is proposed as a biomarker for early detection of colorectal cancer.