Given the natural history of colorectal and breast cancer, early diagnosis appears to be the most appropriate tool to reduce disease-related mortality.[6;7] Currently, there is no early diagnostic... Show moreGiven the natural history of colorectal and breast cancer, early diagnosis appears to be the most appropriate tool to reduce disease-related mortality.[6;7] Currently, there is no early diagnostic test with high sensitivity, specificity and positive predictive value, which can be used as a routine screening tool. Therefore, there is a need for new biomarkers for both types of cancer that can improve early diagnosis, monitoring of disease progression and therapeutic response and detect disease recurrence. Proteomic expression profiles generated with mass spectrometry have been suggested as potential tools for the early diagnosis of cancer and other diseases. Because it is still in its infancy, many problems have to be overcome before clinical proteomics can be transferred form bench to bedside. Chapter 2 gives an insight in the different fields of translational research in colorectal cancer by our group. In chapter 3 reliability of human serum protein profiling using MALDI-TOF mass spectrometry is analysed. We present a pipeline for pre-processing, statistical data analysis and presentation of MALDI-TOF spectra. This novel analysis method was used to assess the effect of variable pre-analytical conditions on human serum protein profiles, and their effect on reproducibility. In line with the logistic conditions in a routine clinical setting, the effects of sample handling and storage, and also circadian rhythm factors on the serum protein profiles were analysed. In chapter 4 and 5 the feasibility of mass spectrometry based protein profiling for the discrimination of colorectal cancer patients from healthy individuals was assessed. In addition to standardizing technical factors and biological variations, we performed blinded tests and employed a randomised block design experimentation to minimize impact of potential confounding factors and to avoid bias. Especially, validation of our classifier, as a possible pitfall, was given much attention. Therefore, we performed a linear discriminant analysis with double cross-validation to separate cancer patients from healthy subjects. Chapter 6 reports on results from an identical designed protein profiling study for the detection of breast cancer. In chapter 7 a first validated study on the detection of breast cancer based on mass spectrometry generated protein profiles is described. In this study the same randomised blocked design and double cross validation is used, however the classifier was validated in an independent set of new patients and controls. Finally, the results and conclusions of all above mentioned studies and especially the current status of clinical proteomics in cancer are discussed in chapter 8. A Dutch summary of this thesis is written in chapter 9. Show less
The current thesis discusses the use of molecular and biological tumor markers to predict clinical outcome. By studying several key processes in the develepment of cancer as regulation of cell... Show moreThe current thesis discusses the use of molecular and biological tumor markers to predict clinical outcome. By studying several key processes in the develepment of cancer as regulation of cell motility (non-receptor protein tyrosin adesion kinases, FAK, Src and paxillin, Apoptosis (caspase-3 activity and M30 expression) and regulation of cell growth (COX-2 expression). In addition the use of selective COX-2 inhibitors for the treatment of colorectal cancer liver metastases is investigated and discussed. The main outcomes of the thesis are that combined FAK/Src immunohistochemical expression is predictive of tumor recurrence in colorectal cancer, but is not overexpressed in liver metastases. Increased tumor cell apoptosis can have a positive or a negative impact on survival and local recurrence, depending on the location of the tumor in the large bowel . In rectal cancer caspase-3 activity can be used to preoperatively select patients who will not benefit from radiation therapy. COX-2 expression in rectal cancer is only of prognostic significance in irradiated rectal cancer patients, not in non-irradiated. Liver metastases in an animal model show deminished growth in the abcence of COX-2 expression and prostaglandin production. 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
