title: How folate metabolism affects colorectal cancer development and treatment; a story of heterogeneity and pleiotropy.
abstract: Folate was identified as an essential micronutrient early in the twentieth century and anti-folate chemotherapy such as 5-fluorouracil (5-FU) has been central to the medical management of solid tumours including colorectal cancer for more than five decades. In the intervening years, evidence has been gathered which shows that folate deficiency leads to many human diseases throughout the life-course. However, we still do not know all of the mechanisms behind functional folate deficiency, or indeed its rescue through supplementation with natural and particularly synthetic folates. There is growing evidence that one adverse effect of folic acid fortification programmes is an increased risk of colorectal cancer within populations. The complexity of folate-dependent, one-carbon metabolism and the heterogeneity that exists between individuals with respect to the enzymes involved in the anabolic pathways, and the catabolism of 5-FU, are explored in this review. The enzyme products of some genes such as MTHFR exert multiple and perhaps unrelated effects on many phenotypes, including cancer development. We describe this pleiotropy and the common genetic variants that affect folate metabolism; and discuss some of the studies that have investigated their potential as predictive biomarkers.
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK. Electronic address: b.jennings@uea.ac.uk.
authors.forename: Barbara Anne
authors.initials: BA
authors.lastname: Jennings
authors.affiliation: Department of Molecular Genetics, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Willis
mesh_terms: D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D005494:Folic Acid Deficiency / Q000235:genetics / Q000378:metabolism*; D018740:Genetic Heterogeneity; D058685:Genetic Pleiotropy; D014644:Genetic Variation; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D005493:Folic Acid Antagonists; D003841:Deoxycytidine; D000069287:Capecitabine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: Colorectal cancer; Folate metabolism; Pharmacogenetics