Our study provides a model of tumour evolution whereby MSH2 or MSH6-deficiency triggers unrestricted mutagenesis at methylated CpGs during the pre-malignant phase of tumour evolution and that the highly sequence-specific CpG hypermutator phenotype converges on TP53 hotspot driver mutations and malignant transformation or relapse due to TP53-deficiency. The gene discussed is MSH2; the disease is neoplasm.