Delocalized DNA holes imprint mutation position in mismatch-repair-deficient cancers

Abstract

One electron oxidation of DNA generates migrating holes that come to rest at guanine runs, a positional pattern of damage characterized in vitro but not shown to reach somatic mutation in human cancer. In mismatch repair deficient gastric, colorectal and endometrial tumours, we find G>T substitutions within guanine runs enriched at the 5' guanine (0.86~0.87) and depleted at the 3' guanine (0.05~0.08), specific to G>T and near identical across all three cancer types. The profile along runs of two to five guanines, including the flattening of the profile as runs lengthen, matches the charge density computed for a delocalized hole without fitting (r = 0.87~0.93); treating the transfer integral as the only free parameter returns 0.073~0.088 eV from four datasets: three tumour cohorts, and mismatch-repair-knockout cells grown without added damage that share no part of the tumour pipeline. A defined one electron oxidant reproduces the asymmetry in repair proficient cells, and the asymmetry is undiminished among clonal mutations, where oxidation introduced during library preparation cannot reach. Guanine ionization energy nonetheless does not predict the genomic distribution of C>A substitutions, in any oxidative stratum of non hypermutated tumours or in the reference signature attributed to reactive oxygen species, delimiting where this chemistry reaches the cancer mutation spectrum.