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
Colorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3%... Show moreColorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3% of all colorectal cancers occur in the setting of a well described autosomal dominant inherited syndrome: The Lynch syndrome. It is essential to identify individuals at increased risk to offer adequate surveillance programs to prevent the development of tumors or recognize them at an early stage. This thesis gives a laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis. Several aspects of surveillance in Lynch syndrome are described. The appropriate screening interval is discussed and the effect on mortality because of surveillance is shown. Further, we sought to establish whether individuals from dominant families without mismatch repair deficiency are also at increased risk by examining the incidence of advanced neoplasia during surveillance. Finally, the prevalence of the frequency of a positive family history for CRC, within a random cohort among the Dutch population is presented and also the prevalence of adenomas among young individuals at average risk for colorectal cancer is shown. Show less
