Strikingly, somatic mutations in the 3′→5′ exonuclease domain of hPolε impair the proofreading activity, cause a high frequency of errors (>10−4 mutations per base) in the leading strand, elevate recurrent nonsense mutation rates in key tumor suppressors, such as TP53, ATM and PIK3R1, and ultimately lead to the formation of various cancers (27). This evidence concerns the gene PIK3R1 and cancer.