Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Abstract

The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.

Complete and Prolonged Response to Immune Checkpoint Blockade in POLE-Mutated Colorectal Cancer

“…4,5 Similarly, accumulating evidence suggests that TMB alone, independent of MMR status, correlates with response to immune checkpoint blockade for some tumor types. 3,[6][7][8][9] Hence, MSS tumors with an ultra-mutated phenotype as a result of mutations in POLE or POLD1 10,11 represent an intriguing subset of tumors that may also respond to immune checkpoint inhibitors.…”

DNA polymerase δ proofreads errors made by DNA polymerase ε

“…The redundancy in replication fidelity mechanisms has implications for human cancer biology. Mutations in the POLE gene, which encodes the catalytic subunit of Pole in humans, are found in 5-8% of sporadic colorectal and endometrial cancers and define a unique subset of these cancers with a so-called ultramutated phenotype (62). The POLE mutations predominantly affect the exonuclease domain of Pole and cause strong mutator and cancer susceptibility phenotypes in model systems (39,63,64).…”

DNA polymerase η mutational signatures are found in a variety of different types of cancer

“…For example, different types of tumor differ strikingly between mouse strains with defective exonucleases of pol d versus pol e 9 or when different members of APOBEC family are expressed, such as activation-induced deaminase AID (predominantly liquid tumors) versus APOBEC3B (breast and other solid tumors) in humans [10][11][12] . The hereditary lack of mismatch repair and/or exonuclease activity of replicative DNA pols predispose to colorectal cancer [13][14][15] ; abnormal DNA double strand break repair leads to an increase in incidence of breast and ovarian cancer 16 ; sunlight and defective pol h cause skin cancer 17 .…”