Adenomatous Polyposis Syndromes: Polymerase Proofreading-Associated Polyposis

Abstract

POLE and POLD1 encode the major subunits of polymerase e and polymerase δ, respectively. Missense germline mutations in the exonuclease domains (EDMs) of POLE and POLD1 have been found to be a rare cause of multiple colorectal adenomas and carcinomas. This condition is known as polymerase proofreading-associated polyposis (PPAP). The EDM of POLE is also somatically mutated in ~1% of colorectal cancers (CRCs) and ~8% of endometrial cancers. In this chapter we will consider the roles of these two enzymes, germline mutations that have been identified to date and their pathogenicity, the characteristics of tumours with germline or somatic mutations, clinical characteristics of patients with PPAP and the potential use of immunotherapy in patients with mutations in the EDM of POLE.