Approximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1,... Show moreApproximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1, NTHL1 and APC contribute to a portion of this risk. However, the genetic basis for 20%-30% of inherited CRC remains unclear. This thesis explores the roles of POLE, POLD1, APC and NTHL1 in CRC and polyposis. While screening for pathogenic variants in POLE and POLD1, remarkably POLE L424V variants were found to induce Lynch syndrome-like features due to somatic mismatch repair gene mutations. Biallelic NTHL1 variants predisposing to CRC and polyposis were studied in a collaborative effort, describing a broad tumor spectrum and a high risk of extracolonic cancers associated with NTHL1 deficiency. For monoallelic NTHL1 variant carriers, no significant evidence link was found with increased polyposis or CRC risk, as supported by mutational signature analysis on colorectal tumors. Show less
In prostate (PCa) and colorectal (CRC) cancer, there is a need to improve patient stratification techniques that aid diagnostic and prognostic decision-making. To fulfill this unmet clinical need,... Show moreIn prostate (PCa) and colorectal (CRC) cancer, there is a need to improve patient stratification techniques that aid diagnostic and prognostic decision-making. To fulfill this unmet clinical need, the measurement of disease-related biological parameters known as “biomarkers” from biofluids is an approach with the potential to develop noninvasive tests as well as achieve greater clinical accuracy and personalized medicine. Thus, this thesis focused on developing a better understanding of biomarkers relevant to PCa and CRC as well as advancing analytical methodology and achieving methodological advancements for the purpose of biomarker discovery. In chapters two and three, a large diversity of prostate-specific antigen (PSA) cleaved and non-cleaved proteoforms (PCa) with different N-glycosylation patterns were determined in urine and seminal fluid using capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS), some of which are relevant for PCa patient stratification. In addition, the data processing workflow was improved in chapter three in order to enable larger studies of intact proteoforms to be performed. Furthermore, chapter four developed a reversed phase-liquid chromatography (RPLC)-MS method whereby it was possible to determine sialic acid linkages and positional isomers in released N-glycans following fluorescent labeling and sialic acid derivatization. This method was applied in chapter five to study serum N-glycosylation profiles in CRC and it was demonstrated that specific N-glycan isomers are implicated in the disease and differences between histological types were eradicated following surgery. Show less
Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. Show less
Glycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells.... Show moreGlycosylation is a widely occurring and complex modification found on lipids and proteins and is involved in the recognition, signaling and interaction events within the cell and between cells. These events based on glycan structures result in adhesion, cell-matrix interaction and immune recognition. Alterations in the glycomic profile are considered a hallmark of various diseases, including cancer where it contributes to the development and progression of cancer, affecting cell-cell communication, cell-matrix interactions, tumor angiogenesis, invasion and metastasis. These functions are governed by different glycans and their terminal structures. In order to further explore these structures with regard to their potential as biomarkers and specific targets for diagnostic applications and therapeutical strategies for various diseases, in-depth glycomic analysis is needed. It is further noted that aberrant glycosylation not only results from the altered expression of glycosyltransferases (GTs) but also from the changed activity of GTs and glycosidases as well as the availability and abundance of sugar nucleotide donors. The aim of the research described in this thesis was to explore the glycomic signatures of colorectal cancer (CRC) in cell lines and tissues as well as of acute myeloid leukemia (AML) cell lines. Show less
Colorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and... Show moreColorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and although immunotherapy has shown promising results in a number of cancer types, not all CRC patients respond well to these treatments. This can in part be attributed to the differences in T cell infiltration between cancers but does not one on one translate to clinical response. Moreover, the activity of specific immune cells can directly influence other immune cells, both in an activating and inhibitory manner. This highlights the complexity of the tumour immune microenvironment and requires an comprehensive multiplex approach to simultaneously investigate all the players of the tumour immune microenvironment. Furthermore, the interaction between different immune cells and between those and cancer cells is essential to take into account, hence the need for an approach that combines multiplex immunophenotyping with spatial cell context. This will provide hints into the behaviour of the players of the tumour immune microenvironment and aid the understanding of CRC, but potentially of other cancer types as well. In this work we developed and applied multispectral immunophenotyping methodologies to strengthen our understanding of CRC Show less
