Extended family with an inherited pathogenic variant in polymerase delta provides strong evidence for recessive effect of proofreading deficiency in human cells

Abstract

Mutational processes in germline and in somatic cells are vastly different, and it remains unclear how the same genetic background affects somatic and transmissible mutations. Here, we estimate the impact of an inherited pathogenic variant in the exonuclease domain of polymerase delta (Pol{delta}) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, the POLD1 L474P variant increases the mutation burden only slightly, contributing [~]11.8% and [~]14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of inherited pathogenic variants in POLD1 harbor a DNA rearrangement that results in a homozygous state of the pathogenic variant, leading to an extremely high mutation rate. Thus, mutations in both alleles of POLD1 gene are required for strong increase in mutation rate suggesting recessiveness of Pold{delta} proofreading. These results show a similar role of Pol{delta} in germline and somatic replication, and, together with previous findings, illustrate the important differences between Pol{delta} and Pol{varepsilon} in the disruption of their replication fidelity.