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Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Lookup NU author(s): Dr Richard Gallon, Rachel Phelps, Christine Hayes, Annabel Kunzemann Martinez, Dr Gillian Borthwick, Professor Sir John BurnORCiD, Dr Michael Jackson, Dr Mauro Santibanez Koref



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Background & aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Publication metadata

Author(s): Gallon R, Phelps R, Hayes C, Brugieres L, Guerrini-Rousseau L, Colas C, Muleris M, Ryan NAJ, Evans DG, Grice H, Jessop E, Kunzemann-Martinez A, Marshall L, Schamschula E, Oberhuber K, Azizi AA, Baris Feldman H, Beilken A, Brauer N, Brozou N, Dahan K, Demirsoy U, Florkin B, Foulkes W, Januszkiewicz-Lewandowska D, Jones KJ, Kratz CP, Lobitz S, Meade J, Nathrath M, Pander HJ, Perne C, Ragab I, Ripperger T, Rosenbaum T, Rueda D, Sarosiek T, Sehested A, Spier I, Suerink M, Zimmermann SY, Zschocke J, Borthwick GM, Wimmer K, Burn J, Jackson MS, Santibanez-Koref M

Publication type: Article

Publication status: Published

Journal: Gastroenterology

Year: 2023

Volume: 164

Issue: 4

Pages: 579-592.e8

Print publication date: 01/04/2023

Online publication date: 29/12/2022

Acceptance date: 02/12/2022

Date deposited: 09/02/2024

ISSN (print): 0016-5085

ISSN (electronic): 1528-0012

Publisher: Elsevier Inc.


DOI: 10.1053/j.gastro.2022.12.017

PubMed id: 36586540


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Funder referenceFunder name
Aspirin for Cancer Prevention (AsCaP) group
Cancer Research UK