Growth in humans, primarily longitudinal growth, is a complex process which starts at conception and proceeds through various developmental stages, mainly controlled by genetic factors and to a... Show moreGrowth in humans, primarily longitudinal growth, is a complex process which starts at conception and proceeds through various developmental stages, mainly controlled by genetic factors and to a lesser degree by environmental, psychosocial and nutritional factors. The GH-IGF-I axis is an important regulator of longitudinal growth, what is evident from the observation that genetic defects in this axis have been shown to be responsible for abnormal growth. These mutations, however, are rare and do not explain the __normal__ variation in height among people. This thesis focuses on the detection of genetic defects in the GH-IGF-I axis that may explain growth disorders. Initially the so-called __candidate gene approach__ was used, examining various genes in the GH-IGF-I axis. After that, a whole genome approach was used to identify novel genes involved in aberrant growth using whole genome microarray studies (SNP-ar rays) and next-generation sequencing. Also, for some genes genotype-phenotype correlations were established. With this we have tried to acquire more insight in the regulation of longitudinal growth Show less
Colon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival)... Show moreColon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival) for stage IV patients and excellent (more than 90% 5 year survival) for stage I patients. The prognosis of patients with stage II varies between 80 and 60% 5-year survival. The causes of this variation remain unclear. Furthermore, the prognosis of patients with stage III has improved significantly, reaching 70% 5-year survival, since the introduction of adjuvant chemotherapy. However, still 30% of the patients with stage III disease that do not respond to chemotherapy. Therefore, reliable predictive and prognostic markers in stage II and III colon carcinoma are necessary to be able to elucidate whether a patient is going to respond to therapy or not and to be able to offer personalized treatment. In this research project, we aimed to identify predictive markers of therapy response in stage III disease and prognostic markers in stage II and III colon carcinoma. The first three chapters focus on the value of known single nucleotide polymorphisms (SNP) in genes involved in the activation, metabolism of chemotherapeutic drugs like 5-fluorouracil and oxaliplatin as well as in the repair of DNA damage caused by these drugs as predictive markers for therapy response. In the remaining chapters , the focus is placed on the identification of molecular prognostic markers in stages II and III. Several mutations in known cancer driver genes and genes involved in signal transduction have been studied. Show less
Conventional karyotyping has been used as the standard cytogenetic technique since the 1970s. With conventional karyotyping one can detect aberrations larger than 5 __ 10 Mb and it can detect... Show moreConventional karyotyping has been used as the standard cytogenetic technique since the 1970s. With conventional karyotyping one can detect aberrations larger than 5 __ 10 Mb and it can detect chromosomal aberrations in approximately 5% of patients with mental retardation (MR). To identify smaller copy number variants (CNVs) new molecular cytogenetic techniques have been developed. One of these techniques is the Single Nucleotide Polymorphism (SNP) array. This method allows the detection of SNP-genotype as well as the presence of small deletions and amplifications. In this thesis we have studied patients with MR and/or congenital malformations. The question we have tried to answer by studying the genome of the patient is whether we can find a cause for the signs and symptoms observed in the patient. The SNP array was successfully used for the detection of novel CNVs and has replaced the conventional karyotyping in the routine diagnostic flow in MR patients in our diagnostic setting. We are therefore able to make a diagnosis in a higher number of MR patients, thus improving medical care and genetic counselling. However, a major complexity is the finding of potentially pathogenic CNVs for which the clinical significance is not immediately clear. Show less
Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of... Show moreEach year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the use of molecular pathology for identifying individuals with an increased risk for CRC based on their genetic makeup, and for generating insight into the tumorigenesis of familial CRC. We conclude that molecular pathology has a high potential for playing an active role in identifying individuals with CRC predisposing syndromes in a diagnostic setting as well as in studying tumorigenesis of CRC in a research setting. Tests which are readily applicable and straightforward, are now extensively used in our daily molecular pathology diagnostics. In the research setting, molecular pathology will be an important player in study the contribution to an increased CRC risk of the susceptibility alleles that are being identified. Furthermore, we now argue that the distinct tumor profiles that we found are convincing examples that molecular pathology approaches are also crucial in the characterization and elucidation of unresolved familial causes of CRC. Show less
