Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy
Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin.
We thank J Flach, I Palmgren and M Akerström for their technical assistance, H Björkqvist and A-L Helminen for the collection of surgical samples and L Munro and B Sjöberg for their work with the clinical database. We also thank personnel at the Genomics Core Facility for performing the quantitative gene expression analysis, and personnel at the Bioin-formatics Core Facility for their help with the statistical analyses. This work was supported by grants from the Swedish Cancer Society, the Health and Medical Care Committee of the Regional Executive Board Region Västra Götaland, Isofol Medical AB, the Assar Gabrielsson Foundation for Cancer Research, the Gustaf V Jubilee Clinic Foundation for Cancer Research, the Anna-Lisa and Bror Björnsson Foundation and the Ingabritt and Arne Lundberg Foundation.
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