POLD1

Overview

POLD1 encodes the catalytic subunit of DNA polymerase delta, a key proofreading polymerase involved in DNA replication and repair. Exonuclease domain mutations in POLD1 produce an ultramutator phenotype similar to POLE mutations, resulting in exceptionally high tumor mutational burden (TMB) and favorable response to immune checkpoint blockade.

Alterations observed in the corpus

  • POLD1 exonuclease domain hotspot mutations were assessed in endometrial carcinoma (EC) as part of the molecular characterization of the POLE/POLD1 ultramutator subtype; this subtype was rare in Black patients (1.2% POLE mutations reported specifically, POLD1 mentioned in the same molecular class) PMID:37651310.
  • Germline susceptibility variant Ser478Asn checked but not found in the TCGA endometrial cancer cohort; POLD1 not a driver in this dataset PMID:23636398
  • No somatic mutations identified across 23 pancreatic acinar cell carcinomas and pancreatoblastomas; wild-type status documented alongside POLE in this exome sequencing cohort PMID:24293293
  • Exonuclease-domain mutations E374K and C284Y observed in NSCLC DCB patients on pembrolizumab; E374K in a never-smoker with the highest never-smoker mutation burden (507 nonsynonymous mutations); C284Y in the highest-burden tumor overall; both lie in the proofreading domain and produce a hypermutator phenotype with Cā†’T predominance distinct from smoking signature PMID:25765070
  • POLD1 proofreading defect identified among mismatch repair / proofreading-deficient hypermutated HNSC tumors in a recurrent/metastatic head and neck NGS cohort PMID:27442865.

Cancer types (linked)

  • Endometrial carcinoma (UCEC) ā€” POLD1 exonuclease domain mutations define the ultramutator subtype with favorable prognosis; this subtype was substantially underrepresented in Black EC patients compared to White patients PMID:37651310.

Co-occurrence and mutual exclusivity

  • POLD1 ultramutator mutations are typically mutually exclusive with POLE mutations and with MSI-H/dMMR; they define a distinct molecular subtype in endometrial carcinoma.

Therapeutic relevance

  • The POLE/POLD1 ultramutator subtype is associated with favorable prognosis and excellent response to immune checkpoint blockade; the underrepresentation of this subtype in Black EC patients may contribute to disparities in immunotherapy eligibility PMID:37651310.

Open questions

  • The mechanistic basis for the lower occurrence of POLE/POLD1 ultramutator ECs in Black patients remains unknown and warrants investigation PMID:37651310.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:23636398

This page was processed by crosslinker on 2026-05-14. - PMID:24293293

This page was processed by crosslinker on 2026-05-14. - PMID:25765070

This page was processed by crosslinker on 2026-05-14. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15.