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Lookup NU author(s): Dr Richard GallonORCiD, Georgie Holt, Dr Waleed Alfailakawi, Dr Akhtar Husain, Peter Sowter, Dr Mauro Santibanez Koref, Dr Michael JacksonORCiD, Professor Sir John BurnORCiD, Professor Neil RajanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Background: One in five patients with sebaceous tumours (STs) may have Lynch syndrome (LS), an inherited disorder that increases the risk of developing cancer. Patients with LS benefit from cancer surveillance and prevention programmes and immunotherapy. While universal tumour mismatch repair (MMR) deficiency testing is recommended in colorectal and endometrial cancers to screen for LS, there is no consensus screening strategy for STs, leading to low testing rates and inequity of care. Objectives: To assess a low-cost and scalable sequencing-based microsatellite instability (MSI) assay, previously shown to enhance LS screening of colorectal cancers, for MMR deficiency detection in STs against the current clinical standard of immunohistochemistry (IHC). Methods: Consecutive ST cases (n = 107) were identified from the records of a single pathology department. MMR protein IHC staining was interpreted by a consultant histopathologist. MSI analysis used amplicon sequencing of 14 microsatellites and a naive Bayesian classifier to calculate the sample MSI score. Results: Loss of MMR protein expression was observed in 49/104 STs with interpretable IHC [47.1%, 95% confidence interval (CI) 37.3-57.2]. MMR deficiency was less frequent in carcinoma than in adenoma and sebaceoma (P = 4.74 × 10-3). The majority of MMR-deficient STs had concurrent loss of MSH2 and MSH6 expression. The MSI score achieved a receiver operator characteristic area under curve of 0.944 relative to IHC. Lower MSI scores were associated with MSH6 deficiency. Conclusions: These data support MSI testing as an adjunct or alternative to MMR IHC in STs. Integration of STs into established LS screening pathways using this high-throughput methodology could increase testing and reduce costs.
Author(s): Gallon R, Holt G, Alfailakawi W, Husain A, Jones C, Sowter P, Santibanez-Koref M, Jackson MS, Burn J, Cook S, Rajan N
Publication type: Article
Publication status: Published
Journal: Clinical and Experimental Dermatology
Year: 2025
Volume: 50
Issue: 6
Pages: 1155-1162
Print publication date: 01/06/2025
Online publication date: 23/01/2025
Acceptance date: 29/12/2024
Date deposited: 25/06/2025
ISSN (print): 0307-6938
ISSN (electronic): 1365-2230
Publisher: Oxford University Press
URL: https://doi.org/10.1093/ced/llaf005
DOI: 10.1093/ced/llaf005
Data Access Statement: FASTQ files generated by the Newcastle MSI-Plus assay and MMR gene MIP amplicon sequencing are available from the European Nucleotide Archive (https://www.ebi.ac.uk/ena/browser/home) using study IDs PRJEB79222 and PRJEB79223, respectively.
PubMed id: 39847610
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