Approximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1,... Show moreApproximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1, NTHL1 and APC contribute to a portion of this risk. However, the genetic basis for 20%-30% of inherited CRC remains unclear. This thesis explores the roles of POLE, POLD1, APC and NTHL1 in CRC and polyposis. While screening for pathogenic variants in POLE and POLD1, remarkably POLE L424V variants were found to induce Lynch syndrome-like features due to somatic mismatch repair gene mutations. Biallelic NTHL1 variants predisposing to CRC and polyposis were studied in a collaborative effort, describing a broad tumor spectrum and a high risk of extracolonic cancers associated with NTHL1 deficiency. For monoallelic NTHL1 variant carriers, no significant evidence link was found with increased polyposis or CRC risk, as supported by mutational signature analysis on colorectal tumors. Show less
