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
Elsayed, F.A.; Tops, C.M.J.; Nielsen, M.; Ruano, I.; Vasen, H.F.A.; Morreau, H.; ... ; Wezel, T. van 2019
Background Germline mutations affecting the exonuclease domains of POLE and POLD1 predispose to colorectal adenomas and carcinoma. Here, we aimed to screen the exonuclease domains to find the... Show moreBackground Germline mutations affecting the exonuclease domains of POLE and POLD1 predispose to colorectal adenomas and carcinoma. Here, we aimed to screen the exonuclease domains to find the genetic causes of multiple colorectal polyps in unexplained cases. Methods Using a custom next-generation sequencing panel, we sequenced the exonuclease domains of POLE and POLD1 in 332 index patients diagnosed with multiple colorectal polyps without germline alteration in colorectal polyposis predisposing genes. Results We identified two variants of unknown significance. One germline POLD1 c.961G>A, p.(Gly321Ser) variant was found in two cases. The first patient was diagnosed with multiple polyps at age 35 and colorectal cancer (CRC) at age 37, with no known family history of CRC. The second patient was diagnosed with CRC at age 44 and cumulatively developed multiple polyps; this patient had two sisters with endometrial cancer who did not carry the variant. Furthermore, we identified a novel POLD1 c.955 T>G, p.(Cys319Gly) variant in a patient diagnosed with multiple colorectal adenomas at age 40. Co-segregation analysis showed that one sister who cumulatively developed multiple adenomas from age 34, and another sister who developed CRC at age 38 did not carry the variant. We did not identify pathogenic variants in POLE and POLD1. Conclusion This study confirms the low frequency of causal variants in these genes in the predisposition for multiple colorectal polyps, and also establishes that these genes are a rare cause of the disease. Show less
Esteban-Jurado, C.; Gimenez-Zaragoza, D.; Munoz, J.; Franch-Exposito, S.; Alvarez-Barona, M.; Ocana, T.; ... ; Castellvi-Bel, S. 2017
