Some studies focused on these tumors (related to somatic MMR mutations, to LS, or to CMMRD (Constitutional MisMatch Repair Deficiency) syndrome, which is caused by biallelic germline MMR mutations) [103,104] and showed that they can acquire a secondarily proofreading defect due to a mutation in the POLE (DNA polymerase epsilon, catalytic subunit) gene, resulting in an ultra-mutant phenotype (>100 mutations/Mb) and a unique mutational signature (“MMR first/POLE second”) [103,104,105]. The gene discussed is POLE; the disease is Constitutional mismatch repair deficiency syndrome.