It was found that in some cancers, defective proofreading due to mutations in the structural domain of the acquired POLE/POLD1 nucleic acid exonuclease results in a significantly higher somatic mutation load with a unique mutational signature, but that in addition to an increased risk of cancer, individuals with germline POLE/POLD1 mutations do not exhibit the telltale features of premature senescence. Here, POLD1 is linked to cancer.