POLD1 and Endometrial Cancer: Molecular Mechanisms, Genomic Pathology, and Emerging Therapeutics

Endometrial cancer (EC) is a major gynecologic malignancy whose classification and treatment paradigms are evolving because of molecular profiling. Mutations in DNA polymerases, particularly in DNA polymerase epsilon (POLE) and DNA polymerase delta 1 (POLD1), have become central to a subset of ultramutated ECs with crucial clinical and prognostic effects. The molecular mechanisms of POLD1 dysfunction in EC, its clinical manifestations, emerging diagnostic challenges, and therapeutic opportunities are explored in this review. Mutations in the exonuclease domain of POLD1 lead to ultramutation. Recent evidence suggests a unique recessive mechanism where an oncogenic mutation is coupled with the loss of the wild-type allele, abrogating the cell's ability to correct replication errors. Mutations in 4 conserved acidic residues (D316, E318, D402, and D515)-the DEDD motif-such as p. D402N result in the loss of proofreading capacity and confer a high tumor mutational burden. Small nuclear ribonucleoprotein polypeptide B overexpression in EC also modulates POLD1 splicing, contributing to its oncogenicity. POLD1-mutant ECs probably represent a subset of the ultramutated molecular category, paralleling POLE-mutated tumors, with implications for diagnostics, genetic counseling, and targeted therapy; their identification necessitates expanded genomic testing, mutational signature analysis, and awareness of their unique splicing and functional biology.