Abstract
Lynch syndrome (LS) is a colorectal cancer predisposition caused by an inherited heterozygous defect in any of four DNA mismatch repair (MMR) genes. MMR prevents nucleotide substitution mutations by correcting errors of replication opposite undamaged or subtly altered nucleotides. Here, we investigated whether dietary mutagens, which generally induce helix-distorting nucleotide lesions, affect LS-associated carcinogenesis. To this aim, we exposed mouse models of LS to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a food-derived heterocyclic amine that selectively adducts guanines. PhIP exposure induced loss of the wild-type MMR allele in heterozygous intestinal stem cells, leading to MMR deficiency and to impaired DNA damage signalling associated with the clonal expansion of MMR-deficient intestinal stem cells. Whole-genome sequencing revealed that PhIP becomes significantly more mutagenic in intestinal stem cells when MMR is lost, inducing not only PhIP-guanine adduct-mediated C:G>A:T transversions but also a broader substitution spectrum that resembles the spontaneous mutational signature of LS-associated colorectal cancer. Thus, MMR corrects PhIP-induced misincorporations outside of adducted guanines. Chronic PhIP exposure of intestine-specific MMR-deficient mice induced adenocarcinomas with histopathological features of LS-associated CRC. This study implicates food-derived mutagens in multiple stages of LS-associated carcinogenesis, including allelic loss, and defective DNA damage signalling and compound hypermutagenesis in the resulting MMR-deficient cells.