Extended family with germline pathogenic variant in polymerase delta provides strong evidence for recessive effect of proofreading inactivation

Abstract

ABSTRACTMutational 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 a germline pathogenic variant in the exonuclease domain of polymerase delta (Polδ) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, the POLD1 L474P variant only slightly increases the mutation burden, contributing to ∼11.8% and ∼14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of germline 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, Polδ proofreading dysfunction has a recessive effect on mutation rate, with mutations in both POLD1 alleles leading to a dramatic rate of mutation accumulation and cancer development. These results clarify the link between the effect of POLD1 mutator variants on germline and somatic replication, and, together with previous findings, illustrate the important differences in disruption of replication fidelity caused by mutations in main replicative polymerases.