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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Background Colorectal cancer (CRC) is the second most common malignancy in developed countries. The mortality is high, with nearly half of patients dying from the disease. The primary treatment of CRC is surgery, and decisions about additional treatment with chemotherapy are based mainly on tumor stage. Novel prognostic markers that identify patients at high risk of recurrence and cancer-related death are needed. The development of CRC has been described in terms of two different pathways; the microsatellite instability (MSI) and chromosomal instability (microsatellite stable, MSS) pathway. More recently, the CpG island methylator phenotype (CIMP), characterized by frequent DNA hypermethylation, has been described as an alternative pathway of tumorigenesis. The event of DNA methylation is dependent on one-carbon metabolism, in which folate and vitamin B12 have essential functions. The purpose of this thesis was to study CIMP in CRC. The specific aims were to investigate the potential role of components of one-carbon metabolism as risk factors for this subgroup of tumors, and the prognostic importance of CIMP status, taking into consideration important confounding factors, such as MSI and tumor-infiltrating T cells. Methods CRC cases and referents included in the Northern Sweden Health and Disease Study (NSHDS, 226 cases and 437 referents) and CRC cases in the Colorectal Cancer in Umeå Study (CRUMS, n=490) were studied. Prediagnostic plasma concentrations of folate and vitamin B12 were analyzed in NSHDS. In both study groups, CIMP status was determined in archival tumor tissue by real-time quantitative PCR using an eight-gene panel (CDKN2A, MLH1, CACNA1G, NEUROG1, RUNX3, SOCS1, IGF2 and CRABP1). MSI screening status and the density of tumor-infiltrating T cells were determined by immunohistochemistry.  Results An inverse association was found between plasma concentrations of vitamin B12 and rectal, but not colon, cancer risk. We also found a reduced risk of CIMP-high and CIMP-low CRC in study subjects with the lowest levels of plasma folate. We found that patients with CIMP-low tumors in both NSHDS and CRUMS had a poorer prognosis compared with CIMP-negative, regardless of MSI screening status. We also found that MSS CIMP-high patients had a poorer prognosis compared with MSS CIMP-negative. The density of tumor-infiltrating T cells and CIMP status were both found to be independent predictors of CRC patient prognosis. A particularly poor prognosis was found in patients with CIMP-low tumors poorly infiltrated by T cells. In addition, the density of T cells appeared to be more important than MSI screening status for predicting CRC patient prognosis. Conclusion Rather than being one disease, CRC is a heterogeneous set of diseases with respect to clinico-pathological and molecular characteristics. We found that the association between risk and plasma concentration of vitamin B12 and folate depends on tumor site and CIMP status, respectively. Patient prognosis was found to be different depending on CIMP and MSI screening status, and the density of tumor-infiltrating T cells.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.

Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.

The purpose of this work was to further understand nutritional status, especially body weight and composition, during colorectal cancer progression. Population-based studies of colorectal cancer patients were conducted using administrative health data (primary and co-morbid diseases, demographics), and computed tomography (CT) imaging (body composition). In cohort 1, administrative health data was used to study comorbidities and nutritional status in 574 colorectal cancer patients referred for chemotherapy. Multivariate Cox regression revealed several comorbidities, performance status and weight loss 20% predicted survival. In cohort 2, a serial CT image analysis assessed longitudinal body composition changes during the last 12 months preceding death from colorectal cancer (n=34). Body composition changes were typified by exponential increases in liver metastases with concurrent accelerations of muscle and fat loss. These results have the potential to make a difference in how colorectal cancer patients are treated and researched by dietitians, oncologists, and health services researchers. / Nutrition and Metabolism