Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA), is a small-to-medium... Show moreAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA), is a small-to-medium vessel vasculitis that affect multiple organs and is life-threatening when untreated. In this thesis, several aspects of ANCA-associated vasculitis concerning genetics, clinical and histopathological classification, treatment and long-term outcome were investigated. Show less
Colorectal cancer is one of the most frequently diagnosed cancers in the Western world. Both hereditary and genetic factors play a role in its etiology. In approximately 3% of colorectal cancer... Show moreColorectal cancer is one of the most frequently diagnosed cancers in the Western world. Both hereditary and genetic factors play a role in its etiology. In approximately 3% of colorectal cancer cases the underlying cause is a hereditary cancer predisposition syndrome called Lynch syndrome. This thesis focuses on an important subset of Lynch syndrome patients, namely those carrying a mutation in the mismatch repair gene PMS2. Relatively little was known about PMS2-associated Lynch syndrome compared to Lynch syndrome caused by other genes. We provide evidence that PMS2 carriers should be considered a separate entity among Lynch patients. First off, PMS2 carriers have a lower penetrance for colorectal and endometrial cancer. Moreover, they are not at increased risk of other Lynch-associated cancers, such as ovarian cancer. The reason for relatively low colorectal cancer penetrance was investigated by analyzing the somatic mutation spectrum of these tumors. This indicated that PMS2 carriers may not develop cancer from so-called mismatch repair deficient crypts. Lastly the effect of lifestyle and single-nucleotide-polymorphisms (SNPs) was investigated which revealed no significant influence on colorectal cancer risk. The results of the studies described in this thesis have resulted in reconsideration of surveillance guidelines of PMS2-associated Lynch syndrome patients. Show less
Dijk, T. van; Baas, F.; Barth, P.G.; Poll-The, B.T. 2018
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... Show moreAn 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. Show less
Verhagen, J.M.A.; Kempers, M.; Cozijnsen, L.; Bouma, B.J.; Duijnhouwer, A.L.; Post, J.G.; ... ; Natl Working Grp BAV TAA 2018
Numerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and... Show moreNumerous studies have contributed to our current understanding of autoimmune diseases (AIDs), however, pathogenesis of many AIDs can still not be fully explained. Both genetic factors and environmental factors are involved in the onset of autoimmunity. Which mechanisms explain the contribution of these genetic and environmental factors to disease pathogenesis, and how the different factors interplay remain unanswered key questions. The studies presented in this thesis aimed at identifying and unravelling some of the enigmatic mechanisms in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Show less
McColgan, P.; Gregory, S.; Seunarine, K.K.; Razi, A.; Papoutsi, M.; Johnson, E.; ... ; Track-On HD Investigators 2018
