Polymerase Epsilon-Associated Ultramutagenesis in Cancer

SIMPLE SUMMARY: DNA polymerase epsilon is implicated to play a major role in DNA synthesis of the leading strand. In some cancer types, especially colorectal and endometrial cancers, polymerase epsilon is mutated at several hotspots, causing large amounts of mutations, termed ultramutation. The aim of this article is to describe the characteristics of polymerase epsilon mutations including their mutation sites and signatures, elucidate the underlying mechanisms of its ultramutagenesis, discuss its good prognosis and favorable responses to immunotherapies, and speculate on possible strategies to improve treatment of ultramutated cancers. ABSTRACT: With advances in next generation sequencing (NGS) technologies, efforts have been made to develop personalized medicine, targeting the specific genetic makeup of an individual. Somatic or germline DNA Polymerase epsilon (PolE) mutations cause ultramutated (>100 mutations/Mb) cancer. In contrast to mismatch repair-deficient hypermutated (>10 mutations/Mb) cancer, PolE-associated cancer is primarily microsatellite stable (MSS) In this article, we provide a comprehensive review of this PolE-associated ultramutated tumor. We describe its molecular characteristics, including the mutation sites and mutation signature of this type of tumor and the mechanism of its ultramutagenesis. We discuss its good clinical prognosis and elucidate the mechanism for enhanced immunogenicity with a high tumor mutation burden, increased neoantigen load, and enriched tumor-infiltrating lymphocytes. We also provide the rationale for immune checkpoint inhibitors in PolE-mutated tumors.