Also, the mutational signatures associated with POLE/POLD1 exonuclease domain defects have been reproduced in vitro in tumor PDOs with a POLE hotspot mutation (Yan et al., 2020), POLE CRISPR-edited cells (Hodel et al., 2020) and POLD1 patient-derived fibroblasts (Andrianova et al., 2022). Here, POLD1 is linked to neoplasm.