Mutagenicity of folic acid deficiency and supplementation is tissue-specific and results in distinct mutation profiles

Abstract

Cancer incidence varies by tissue due to differences in environmental risk factor exposure, gene variant inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia. Conversely, high folic acid (FA) intake has been associated with higher CRC risk. However, the mutagenic potential of FA intake in different tissues has not been characterized. Here we quantified mutations in folate-susceptible somatic tissues, namely bone marrow and colon, from the same MutaMouse mice and determined the FA-induced mutation profiles of both tissues using next generation sequencing. FA-induced mutagenesis was tissue- and dose-specific: FA deficiency increased mutant frequency (MF) in bone marrow while FA supplementation increased MF in colon. Analyses of mutation profiles suggested that FA interacted with mutagenic mechanisms that are unique to each tissue. These data illuminate potential mechanisms underpinning differences in susceptibility to FA-related cancers.