An estimated 15-25% of patients with colorectal cancer have a positive family history, but no known underlying genetic cause. In this thesis we aimed to detect the underlying genetic cause in patients with suspected Lynch Syndrome, a familial disorder caused by mutations in the mismatch repair (MMR) genes. We hypothesized that these patients could be explained by missed MMR variants, somatic inactivation of the MMR genes, or variants in other genes, leading to secondary MMR-deficiency. In our cohort we found 10 patients with two somatic MMR variants in the tumor and 9 patients with a germline or somatic mutation in the POLE or POLD1 genes. Variants in the exonuclease domain of these genes results in highly mutated tumors. Additionally, we describe how to assess the effect of splice variants, and how to sequence the complex PMS2 gene with next generation sequencing. In the second part we aimed to detect the underlying genetic...
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An estimated 15-25% of patients with colorectal cancer have a positive family history, but no known underlying genetic cause. In this thesis we aimed to detect the underlying genetic cause in patients with suspected Lynch Syndrome, a familial disorder caused by mutations in the mismatch repair (MMR) genes. We hypothesized that these patients could be explained by missed MMR variants, somatic inactivation of the MMR genes, or variants in other genes, leading to secondary MMR-deficiency. In our cohort we found 10 patients with two somatic MMR variants in the tumor and 9 patients with a germline or somatic mutation in the POLE or POLD1 genes. Variants in the exonuclease domain of these genes results in highly mutated tumors. Additionally, we describe how to assess the effect of splice variants, and how to sequence the complex PMS2 gene with next generation sequencing. In the second part we aimed to detect the underlying genetic cause in patients with unexplained adenomatous polyposis. By testing multiple adenomas, we found that if two or more adenomas carry the same variant in the APC gene, this was indicative of an underlying mosaic genetic cause. Nine patients with 21-100 adenomas could be explained by APC mosaicism.
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