Furthermore, the indispensability of Polδ for replication of both the DNA strands (3) explains the dearth of somatic Polδ proofreading domain mutations; and the requirement of Polε proofreading activity for the removal of specific Polδ generated mispairs on the leading strand explains the high prevalence of somatic Polε proofreading domain mutations that occur in cancer genomes (29). The gene discussed is POLE; the disease is cancer.