POLE

Overview

POLE encodes the catalytic and proofreading subunit of DNA polymerase epsilon. Hotspot mutations in the exonuclease domain (e.g., P286R, V411M, F367S) abrogate proofreading activity and produce an ultramutator phenotype with extremely high TMB (often >100 mut/Mb). POLE-mutant tumors are exquisitely sensitive to immune checkpoint blockade and carry a favorable prognosis in endometrial cancer.

Alterations observed in the corpus

  • POLE exonuclease domain hotspot mutations rare in Black endometrial cancer patients (1.2% vs. 5.8% in White patients); this favorable-prognosis subtype is substantially underrepresented in the Black EC population, contributing to disparities in access to immunotherapy-eligible molecularly favorable tumors PMID:37651310.
  • One POLE exonuclease domain hotspot mutation (p.F367S) identified in an MSS gynecologic cancer patient; this patient had the highest TMB in the cohort and was MSS, confirming POLE mutation as an independent route to hypermutation PMID:38653864.
  • Three prostate cancer patients harbored oncogenic POLE mutations (P286R ×2, V411M ×1; TMBs of 183, 34, and 169 mut/Mb), all with microsatellite-stable tumors; none of the ICB-treated patients in this cohort had POLE mutations PMID:38949888.
  • POLE exonuclease-domain mutations (e.g. V411L) explain discordant MiMSI MSI calls in pan-cancer NGS data: two MiMSI false-negatives had POLE-deficient mutational signatures plus high TMB; one false-positive (Sample_54409, colon adenocarcinoma) attributed 72% of mutations to POLE deficiency. MiMSI can flag MMR phenotype even when co-occurring with POLE-driven hypermutation. PMID:39746944
  • p.E830G missense mutation in a myoepithelial carcinoma patient (Patient 2) PMID:36577525
  • POLE assessed in metastatic UC (UC-GENOME cohort) in the context of tumor mutational burden and DNA repair pathway analysis PMID:36333289
  • Somatic mutations in the ultramutated subset of colorectal tumors lacking MSI-H; defines a distinct hypermutation mechanism in the 276-tumor TCGA CRC cohort PMID:22810696
  • Exonuclease-domain hotspots Pro286Arg and Val411Leu define the ultramutated endometrial cancer subgroup (Q=4.2×10⁻²³); associated with C→A transversion-rich mutational spectrum and improved progression-free survival PMID:23636398
  • No somatic mutations identified across 23 pancreatic acinar cell carcinomas and pancreatoblastomas; wild-type status documented alongside POLD1 in this exome sequencing cohort PMID:24293293
  • POLE inactivating mutation in one hypermutator gastric cancer case consistent with prior TCGA findings in CRC/endometrial PMID:25079317
  • Absent in 39-case aggressive cSCC cohort — explicit negative finding PMID:25303977
  • Deleterious mutation identified in one of three NSCLC DCB responders with the highest mutation burden on pembrolizumab; supports a DNA-repair–driven hypermutator mechanism for anti-PD-1 benefit in never-smokers PMID:25765070
  • In PAAD, POLE was among the mismatch-repair/DNA-repair gene alterations in the top mutation-burden quartile of the 109-case microdissected exome cohort, contributing to the hypermutator phenotype. PMID:25855536
  • V411L exonuclease-domain hotspot in a single ultramutator upper tract urothelial carcinoma (UTUC) with 422 somatic mutations and no focal CNAs. PMID:26278805
  • POLE observed as a low-frequency hit (>=2 ATC or >=3 PDTC) in a targeted-sequencing study of advanced thyroid cancers (PDTC and ATC). PMID:26878173
  • Exonuclease-domain hotspot mutations (p.Pro286Arg, p.Val411Leu, p.Ser459Phe) found in 4 MSS colorectal carcinoma samples (619-case WES cohort from NHS/HPFS); carriers had elevated neoantigen load and were excluded from MSS-restricted TIL analyses. POLE-mutated CRCs were too few for survival statistics but proposed as candidates for checkpoint blockade based on neoantigen burden. PMID:27149842
  • Loss-of-function somatic mutations underlie POLE-signature hypermutation, predominantly in colorectal and endometrial cancer, across 10,336 MSK-IMPACT cases PMID:28481359
  • No exonuclease-domain hotspot mutations detected in clear-cell endometrial carcinoma (CCEC; n=63); one non-hotspot frameshift (H1901Lfs*15) without ultramutated phenotype, contrasting with POLE-driven hypermutation in endometrioid endometrial cancer PMID:28485815
  • One LGTa NMIBC harbored a truncating H1901Lfs*15 mutation deemed likely non-functional (3’ end, no hypermutation phenotype); no POLE-exonuclease hotspot mutations found in this NMIBC cohort (n=105) PMID:28583311
  • Mutated in 2 of 3 hypermutator cholangiocarcinomas alongside MSI mutational signatures; hypermutator subtype represents a candidate for immune-checkpoint blockade PMID:28667006
  • Somatic POLE mutation explains one of two hypermutator medulloblastomas (ICGC_MB62) in a 491-sample pan-MB WGS/WES cohort; the MLH1-mutant case illustrates an alternate MMR-deficiency hypermutator mechanism PMID:28726821
  • POLE P286R mutation in a single ultra-mutated MIBC tumor (>4000 SNVs), defining the POLE mutational-signature subset PMID:28988769
  • Exonuclease-domain hotspots P286R, S459F, V411L defined the ultra-mutated subgroup (n=8, 0.7%) in 1,640 mCRC tumors; ultra-mutated cases were typically early-stage and male PMID:29316426
  • POLE listed among antigen-presentation and immunology genes profiled in NSCLC patients evaluated for TMB and anti-PD-(L)1 benefit (n=240) PMID:29337640
  • POLE-mutant tumors (together with MSI) drive the apparent pan-cancer anti-correlation between mutation rate and aneuploidy; excluding POLE-mutant hypermutators from 10,522 TCGA samples flips the correlation positive (Spearman rho = 0.38) PMID:29622463.

Cancer types (linked)

  • Endometrial carcinoma (UCEC) — POLE exonuclease domain mutations define the ultramutator subtype with favorable prognosis; underrepresented in Black patients (1.2% vs. 5.8%) PMID:37651310.
  • Gynecologic cancers (UCEC / OVT) — POLE p.F367S generates extreme TMB in the MSS background, representing a distinct hypermutation mechanism PMID:38653864.
  • Prostate cancer (PRAD) — POLE mutations (P286R, V411M) produce TMB-H/MSS phenotype; not clearly associated with ICB benefit in this small series PMID:38949888.
  • Pan-cancer (MSK-IMPACT) — POLE deficiency co-occurs with dMMR in rare cases; MiMSI detects the MMR component even when POLE ultramutation dominates the mutational landscape. Colon adenocarcinoma exemplar had 72% POLE-attributed mutations alongside MSH2 E580* truncation. PMID:39746944

Co-occurrence and mutual exclusivity

  • POLE ultramutator mutations are typically mutually exclusive with MSI-H/dMMR; they produce TMB-H/MSS tumors with a distinct mutational signature.
  • In prostate cancer, POLE mutations were absent from the ICB-treated patient cohort, limiting conclusions about response PMID:38949888.

Therapeutic relevance

  • POLE ultramutator endometrial cancers have favorable prognosis and excellent response to immune checkpoint blockade regardless of MSI status; POLE mutation is an FDA-recognized tumor-agnostic biomarker for pembrolizumab.
  • The underrepresentation of POLE-mutant ECs in Black patients reduces immunotherapy eligibility in this population PMID:37651310.
  • In prostate cancer, the clinical significance of POLE mutations for ICB response is uncertain; TMB-H/MSS prostate cancer does not appear to respond as well to ICB as MSI-H/dMMR disease PMID:38949888.

Open questions

  • The mechanistic basis for the lower occurrence of POLE ultramutator ECs in Black patients remains unknown PMID:37651310.
  • Whether POLE-mutant prostate cancers are a subset of TMB-H/MSS that respond better to ICB requires evaluation in larger cohorts PMID:38949888.

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15. - PMID:29337640

This page was processed by entity-page-writer on 2026-05-15. - PMID:29622463

This page was processed by wiki-cli on 2026-05-15.