Polymerase Epsilon-Associated Ultramutagenesis in Cancer

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.

Keywords: cancer; immunotherapy; polymerase epsilon; prognosis; ultramutagenesis.

Figure 1

Proposed mechanism of good prognosis in PolE associated cancer. PolE encodes the catalytic and proofreading exonuclease subunit of DNA polymerase ε (Pol ε), which is responsible for bulks of DNA synthesis in the leading strand during DNA replication. Cancer-associated PolE mutations in the exonuclease domain hinder proofreading activity and increase polymerase activity, resulting in ultramutation [22,23,24,25]. Subsequently, they lead to an increased neoantigen load [44,47]. When neoantigens are presented, the immune system recognizes them and ultimately generates an immune response, eliciting tumor suppressor function [44,47].