Novel microsatellite instability test of sebaceous tumours to facilitate low-cost universal screening for Lynch syndrome

Sep 23, 2026

Background: One in five patients with sebaceous tumours (STs) may have Lynch syndrome (LS), which increases cancer risk; LS patients benefit from surveillance, prevention, and immunotherapy. Universal mismatch repair (MMR) deficiency testing is standard for colorectal and endometrial cancers, yet no consensus exists for STs, resulting in low testing rates and inequitable care. Objectives: Evaluate a low-cost, scalable sequencing-based microsatellite instability (MSI) assay for MMR deficiency detection in STs versus immunohistochemistry (IHC).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphical Abstract

What is already known about this topic?

What does this study add?

Introduction

Novel microsatellite instability test of sebaceous tumours to facilitate low-cost universal screening for Lynch syndrome Richard Gallon,1 Georgie Holt,1 Waleed Alfailakawi,1 Akhtar Husain,2 Claire Jones,2 Peter Sowter,1 Mauro Santibanez-Koref,3 Michael S Jackson,3 John Burn,1 Sam Cook2 and Neil Rajan1,4 1Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 2 Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 3 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 4 Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK Correspondence: Richard Gallon. Email: [richard.gallon@newcastle.ac.uk](richard.gallon@newcastle.ac.uk) [R.G.](R.G.), G. H. and W.A. contributed equally. Abstract 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 . Graphical Abstract Accepted: 29 December 2024 © The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists . This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1156 Microsatellite instability testing of sebaceous tumours, R. Gallon et al. What is already known about this topic? • Tumour mismatch repair (MMR) deficiency testing can be used to screen for Lynch syndrome (LS), an inherited disorder that increases the risk of developing cancer. • Universal testing for LS is recommended for colorectal and endometrial cancers but not for sebaceous tumours (STs), despite LS being sixfold more prevalent among patients with STs . • Only 34% of sebaceous carcinomas were tested for LS in England in 2018, highlighting a disparity in LS screening between visceral and cutaneous malignancies . What does this study add? • We assessed a novel, low-cost and scalable MMR deficiency test for sebaceous tumours, the Newcastle MSI-Plus assay. • The MSI-Plus assay demonstrated equivalence as an MMR deficiency test com

FAQs

Why is screening for Lynch syndrome important in sebaceous tumours?

Up to one in five patients with sebaceous tumours may have Lynch syndrome, which increases cancer risk. Screening enables surveillance, prevention, and immunotherapy benefits, but testing for STs is currently inconsistent and often low.

How does the study assess mismatch repair deficiency in sebaceous tumours?

It compares a sequencing-based microsatellite instability (MSI) assay with the current clinical standard, mismatch repair (MMR) protein immunohistochemistry (IHC). MSI is calculated using amplicon sequencing of 14 microsatellites and a naive Bayesian classifier.

What did the results show about the MSI assay performance?

Loss of MMR protein expression was observed in 49/104 STs with interpretable IHC. The MSI score showed strong discrimination against IHC, with a receiver operator characteristic area under the curve of 0.944, and lower MSI scores were linked to MSH6 deficiency.

Sep 23, 2026

Uploaded by Alex Sinclair