POLE and cancer: Deleterious germline and somatic mutations, i.e., nonsense and frameshift insertion/deletion (indel) alterations, in six hypermutator genes consisting of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and two DNA polymerase genes with proofreading function, POLD and POLE, were examined as potentially responsible for high TMB, since their aberration is established as associated with high TMB in a variety of human cancers [21-24].