Intriguingly, the initial seven signatures, which were computationally derived from MMRd colon cancer, and then appeared to ‘merge’ in the experimentally obtained ‘universal’ signature RefSig MMR1, might represent distinct and separable mutational mechanisms. For example, our results demonstrate that C > T-dominated SBS44 and T > C-dominated SBS26 are up- and down-regulated in an opposing manner in MSH2-/- ATAD5-/- and MSH2-/- FANCD2-/- double knockouts. Here, MSH2 is linked to malignant colon neoplasm.