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Lookup NU author(s): Peter Sowter, Dr Richard GallonORCiD, Christine Hayes, Rachel Phelps, Dr Gillian Borthwick, Shaun Prior, Dr Mauro Santibanez Koref, Dr Michael Jackson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 by the authors.Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC (n = 196) and Manchester PETALS (n = 165) trials, where concordance between assays differed significantly. Methods: Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL_MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data. Results: NCL_MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL_MSI was significantly associated with MLH1 promoter methylation status (p = 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both (p = 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p = 0.009 Ohio, p = 6.2 × 10−5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs (p = 0.002). Conclusions: These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.
Author(s): Sowter P, Gallon R, Hayes C, Phelps R, Borthwick G, Prior S, Combe J, Buist H, Pearlman R, Hampel H, Goodfellow P, Evans DG, Crosbie EJ, Ryan N, Burn J, Santibanez-Koref M, Jackson MS
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2024
Volume: 16
Issue: 23
Online publication date: 26/11/2024
Acceptance date: 18/11/2024
Date deposited: 09/01/2025
ISSN (electronic): 2072-6694
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/cancers16233970
DOI: 10.3390/cancers16233970
Data Access Statement: All FASTQ files are available from the EMBL-EBI European Nucleotide Archive, Project Accession reference PRJEB79220
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