# POLE ultramutation (POLEmut)

Source: https://onco.cc/terms/pole-ultramutation/  
OnCo record `pole-ultramutation` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A pathogenic mutation in the proofreading part of the POLE gene gives an endometrial tumour hundreds of mutations per megabase and, paradoxically, one of the best outlooks of any womb cancer, so finding it can spare a woman chemotherapy or radiotherapy.

## Summary

What is measured: a pathogenic mutation in the exonuclease (proofreading) domain of DNA polymerase epsilon, at hotspots such as P286R, V411L, S297F, A456P and S459F. How: targeted sequencing of tumour DNA; it is the first step of the ProMisE and WHO 2020 molecular classification and is read before p53 and mismatch repair immunohistochemistry because a POLE mutation trumps an abnormal p53 or a mismatch repair loss found alongside it. About 7 to 8 percent of endometrial carcinomas, mostly early stage and often high grade under the microscope yet with near-zero recurrence: the PORTEC-3 molecular analysis found almost no relapses in the POLEmut group whichever adjuvant treatment was given. The tumours are ultramutated (over 100 mutations per megabase), heavily infiltrated by lymphocytes, and respond to immune checkpoint inhibitors in the rare advanced case. What a positive result changes: de-escalation, tested in PORTEC-4a and the RAINBO POLEmut-BLUE trial, where stage I to II POLEmut cancers receive no adjuvant therapy; non-pathogenic POLE variants outside the domain do not count. Where it matters: the POLE-ultramutated endometrial page, advanced and recurrent endometrial cancer, uterine carcinosarcoma (rare, favourable); also rare colorectal and glial tumours.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: POLE; POLE mutation; POLE-mutated; POLEmut; POLE exonuclease domain mutation; POLE EDM; ultramutated; ultramutation; POLE ultramutated; POLE hotspot mutation

## Notes

- Colorectal cancer: pathogenic somatic POLE exonuclease-domain mutations in 66 of 6,517 cancers (1.0%), mutually exclusive with mismatch repair deficiency and found in younger, more often male patients with earlier-stage disease; the tumours carry CD8 infiltration as high as mismatch repair deficient ones and a recurrence hazard ratio of 0.34 (Domingo 2016). On cBioPortal the hotspot cases carry a median tumour mutational burden of 172.1 per megabase against 5.7 in microsatellite-stable disease. Because they are microsatellite stable, neither immunohistochemistry nor MSI testing finds them; only sequencing does. Germline POLE p.Leu424Val and POLD1 p.Ser478Asn are the inherited form (Palles 2013).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/POLE_(gene)
- Wikipedia: https://en.wikipedia.org/wiki/POLE_(gene)

## Connected records

- terms: [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [No specific molecular profile (NSMP) endometrial cancer](https://onco.cc/terms/nsmp/), [TP53-mutated (p53-abnormal)](https://onco.cc/terms/tp53-mutated/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- drugs: [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- cancers: [Advanced or recurrent endometrial cancer](https://onco.cc/cancers/advanced-recurrent-endometrial-cancer/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [POLE-ultramutated endometrial cancer](https://onco.cc/cancers/endometrial-pole-ultramutated/), [Uterine carcinosarcoma](https://onco.cc/cancers/uterine-carcinosarcoma/)
- key papers: [Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas](https://onco.cc/key-papers/paper-palles-germline-pole-pold1-proofreading-nat-genet-2013/), [Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer](https://onco.cc/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/)
- targets: [POLD1](https://onco.cc/targets/pold1/), [POLE](https://onco.cc/targets/pole/)

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