Mismatch in testing: a retrospective analysis of mismatch repair testing in endometrial cancer and Lynch syndrome diagnosis in multiple specialist centres in the UK and Ireland (March 2022-March 2023)

Neil Ryan^{1

2

3}, Kane Alexander Lennie^#³, Adam Naskretski^#⁴, Craig Anderson^#⁵, Lorena Mihaita^#³, Sanduni Abeysuriya^#⁶, Maria Ashworth^#⁷, Victoria Cullimore^#⁸, Lucy Dobson^#⁹, Nathan Graham^#¹⁰, Radha Graham^#⁶, Shaun Haran^#¹¹, Zuzanna Holwek^#¹², Ashton Hunt^#¹¹, Ben Johnston^#⁵, Rebecca Karkia^#⁷, Georgios Kouklidis^#¹³, Elaine Leung^#¹², Aiste McCormick^#⁵, Josh McMullan^#⁴, Aileen Mohan^#¹⁴, Alison Montgomery^#⁸, Claire Newton^#⁸, Manolis Nikolopoulos^#¹³, Catriona Norden^#¹⁵, Charlotte Nott^#⁵, Gemma Owens^#⁴, Phillip Rolland^#¹², Sammuel Ricketts^#⁹, Vanitha Sivalingam^#⁹, David Smith^#⁵, Freweini Tesfai^#⁶, Laura Tookman^#¹⁶, Chenai Whacha^#¹³, Peter Sanderson³

Affiliations

¹ Centre for Reproductive Health, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
² The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
³ Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK.
⁴ Cardiff and Vale University Health Board, Cardiff, UK.
⁵ Glasgow Royal Infirmary, Glasgow, UK.
⁶ University College London Hospitals NHS Foundation Trust Women's Health Service, London, UK.
⁷ Royal Surrey NHS Foundation Trust, Guildford, UK.
⁸ St Michael's Hospital Gynae Cancer, Bristol, UK.
⁹ Liverpool Women's Hospital NHS Foundation Trust, Liverpool, UK.
¹⁰ Antrim Area Hospital, Antrim, UK.
¹¹ Hammersmith Hospitals NHS Trust, London, UK.
¹² Cheltenham General Hospital, Cheltenham, UK.
¹³ Poole Hospital NHS Foundation Trust, Poole, UK.
¹⁴ Royal United Hospital Bath NHS Trust, Bath, UK.
¹⁵ Craigavon Area Hospital Group Trust, Portadown, UK.
¹⁶ Medical Oncology, Imperial College Healthcare NHS Trust, London, UK.

^# Contributed equally.

PMID: 40510444
PMCID: PMC12161352
DOI: 10.1136/bmjonc-2024-000688

Mismatch in testing: a retrospective analysis of mismatch repair testing in endometrial cancer and Lynch syndrome diagnosis in multiple specialist centres in the UK and Ireland (March 2022-March 2023)

Neil Ryan et al. BMJ Oncol. 2025.

. 2025 Jun 9;4(1):e000688.

doi: 10.1136/bmjonc-2024-000688. eCollection 2025.

Authors

Affiliations

¹ Centre for Reproductive Health, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
² The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
³ Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK.
⁴ Cardiff and Vale University Health Board, Cardiff, UK.
⁵ Glasgow Royal Infirmary, Glasgow, UK.
⁶ University College London Hospitals NHS Foundation Trust Women's Health Service, London, UK.
⁷ Royal Surrey NHS Foundation Trust, Guildford, UK.
⁸ St Michael's Hospital Gynae Cancer, Bristol, UK.
⁹ Liverpool Women's Hospital NHS Foundation Trust, Liverpool, UK.
¹⁰ Antrim Area Hospital, Antrim, UK.
¹¹ Hammersmith Hospitals NHS Trust, London, UK.
¹² Cheltenham General Hospital, Cheltenham, UK.
¹³ Poole Hospital NHS Foundation Trust, Poole, UK.
¹⁴ Royal United Hospital Bath NHS Trust, Bath, UK.
¹⁵ Craigavon Area Hospital Group Trust, Portadown, UK.
¹⁶ Medical Oncology, Imperial College Healthcare NHS Trust, London, UK.

^# Contributed equally.

PMID: 40510444
PMCID: PMC12161352
DOI: 10.1136/bmjonc-2024-000688

Abstract

Objectives: To assess the implementation of Lynch syndrome testing in endometrial cancer (EC) across the UK and Ireland, identify diagnostic gaps and evaluate adherence to the National Institute for Health and Care Excellence (NICE) guidelines recommending routine mismatch repair (MMR) deficiency testing.

Methods and analysis: A multi-centre, cross-sectional retrospective study conducted in line with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. Secondary care cancer centres across the UK and Republic of Ireland were identified with support from the ARGO (Audit and Research in Gynaecological Oncology) Collaborative and invited to complete a bespoke data collection tool.

Results: Data from 2716 histologically confirmed EC cases treated between March 2022 and March 2023 were collected. After excluding misdiagnosed and inconsistent cases, 2549 were analysed. The cohort had a mean age of 66.3 years and a mean body mass index of 33.43 kg/m²; 69.3% had endometrioid EC histology. MMR testing was performed in 91% of cases, with 27.6% classified as MMR deficient, mainly due to MLH1/PMS2 loss (77.4%). Of the 510 cases requiring hypermethylation analysis, results were missing for 62. Of the 181 participants eligible for genetic counselling, 64% were referred and 48% underwent germline testing, identifying 19 new Lynch syndrome cases. MMR-deficient tumours were diagnosed at earlier stages and lower grades compared with MMR-proficient tumours.

Conclusions: While tumour based MMR testing is widely performed, diagnostic attrition significantly impairs the pathway to definitive Lynch syndrome diagnosis. Addressing barriers to genetic counselling and germline testing is crucial for improving patient outcomes and the cost-effectiveness of Lynch syndrome screening.

Keywords: Genetic markers; Immunotherapy; Uterine cancer.

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Conflict of interest statement

None declared.

Figures

Figure 1. Patient testing outcomes. ^∧Two known LS carriers removed. ^∧∧One patient died before could get results. *Four patients with known LS removed. **One VUS. ***Three declined/did not attend their appointment. *****Five declined. ^∧∧∧One patient with known LS removed. LS, Lynch syndrome; PRHM, promoter region hypermethylation. VUS: Variant of Unknown Significance

See this image and copyright information in PMC

References

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1. Ryan NA, McMahon RF, Ramchander NC, et al. Lynch syndrome for the gynaecologist. Obstet Gynaecol . 2021;23:9–20. doi: 10.1111/tog.12706. - DOI - PMC - PubMed

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Mismatch in testing: a retrospective analysis of mismatch repair testing in endometrial cancer and Lynch syndrome diagnosis in multiple specialist centres in the UK and Ireland (March 2022-March 2023)

Affiliations

Mismatch in testing: a retrospective analysis of mismatch repair testing in endometrial cancer and Lynch syndrome diagnosis in multiple specialist centres in the UK and Ireland (March 2022-March 2023)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources