Diagnostic Pathology - Case Report - A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer

Sep 24, 2026

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Defect in proofreading exonuclease activity of polymerases epsilon and delta (POLE and POLD1) drives mutagenesis and genomic instability and has been documented across multiple cancers. Somatic POLE exonuclease domain mutations define an endometrial cancer subgroup with ultrahigh mutation frequencies, lymphocyte-rich tumors, and favorable clinical outcomes. This case report describes a novel POLE exonuclease domain mutation p.T278K identified by targeted NGS and explains molecular inconsistencies between MSI testing and MMR immunohistochemistry.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages5

Reading Time13 min

AccessFree to download

Background

Somatic POLE exonuclease domain mutations in EC

Case presentation

Identification of p.T278K and NGS panels

MSI versus MMR IHC inconsistency

MSH6 nonsense mutations and protein truncation

Conclusions

Molecular analyses

Next generation sequencing on FFPE tissue

Cui et al. Diagnostic Pathology (2023) 18:19 [https://doi.org/10.1186/s13000-023-01287-y](https://doi.org/10.1186/s13000-023-01287-y) Diagnostic Pathology CASE REPORT Open Access A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report Jiantao Cui1, Xiuying Chen1, Qian Zhai1, Na Chen1, Xiaodan Li1, Yuli Zhang1, Hui Wang1, Xin Bian 1, Na Gao1, Deyi Chen2, Zhihong Chen2, Shibiao Zhang1* andYan Chen2* Abstract Background Defect in proofreading exonuclease activity of polymerases epsilon and delta (Pols ε and δ) leads tomutagenesis and genomic instability and has been described in several cancer types. Somatic POLE exonuclease domain mutations (EDMs) have been reported in 7–12% endometrial cancers (ECs) and defined a subgroup of endometrial cancers with ultrahigh somatic mutation frequencies, high tumor infiltrated lymphocytes and favorable outcomes. Case presentation Herein, we presented a novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer. A novel POLE EDM (p.T278K) was found by a 11-gene NGS panel. The MSS status detected by the MSI test was inconsistent with the dMMR status by IHC. The loss of MSH6 expression in the tumor could be interpreted by the two nonsense mutations (p. E1234* and p. E1322*) of the MSH6 gene which may lead to truncated proteins. The T278K mutation was pathogenic identified by a 602-gene NGS panel with 27. 3% of C >A substitution, 0 . 6% of indels, 0. 6% of C >G substitution and a high TMB of 203.8 mut/Mb. Conclusions We report an endometrial cancer patient harbored a novel somatic POLE T278K mutation. This mutation was a novel pathogenic POLE EDM should be considered as “POLE (ultramutated)”in clinical practice for the molecular classification of EC. Keywords Endometrial cancer, POLE EDM, Hypermutated, TMB *Correspondence: Shibiao Zhang [shibiaozhang2022@163.com](shibiaozhang2022@163.com)[ ](shibiaozhang2022@163.com)Yan Chen [yan.chen@ispacegen.com](yan.chen@ispacegen.com) 1 Department of gynaecology, Cangzhou Hospital of Intergarted TCMWM, 061000 Cangzhou, Hebei, China 2 Xiamen Spacegen Co., Ltd, 361100 Xiamen, China Background Defect in proofreading exonuclease activity of polymerases epsilon and delta (Pols ε and δ) leads to mutagenesis and genomic instability and has been described in several cancer types [1, 2]. Germline mutations in the exonuclease domain of Pol ε (POLE) and δ (POLD1) predispose to colorectal cancer (CRC) and other types of cancer [3, 4]. Somatic POLE exonuclease domain mutations (EDMs) have been reported in 7–12% endometrial cancers (ECs) and 1–2% CRC [3–5]. In 2013, the TCGA study identified four molecular subtypes of EC at genomic level © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[http://creativeco](http:

FAQs

What novel mutation is reported, and how was it detected?

The report identifies a novel somatic POLE exonuclease domain mutation p.T278K. It was found using an 11-gene NGS panel, and pathogenicity was supported by a 602-gene NGS panel.

Why are MSI status and MMR IHC status described as inconsistent?

The MSI test showed MSS status, while IHC indicated dMMR status. The tumor’s MSH6 loss was interpreted in relation to two MSH6 nonsense mutations (p.E1234* and p.E1322*), which may yield truncated proteins.

What molecular features support an ultramutational (POLE-ultramutated) phenotype?

The case shows a high tumor mutational burden (TMB of 203.8 mut/Mb) with a predominance of C>A substitutions and low indel proportions, aligning with described ultramutational POLE signatures.

Sep 24, 2026

Uploaded by hdkawk