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

• DOI: 10.1053/j.gastro.2022.12.017
• Publication Date: 2022-12-29T00:53:28Z
• Authors: Richard Gallon; Rachel Phelps; Christine Hayes; Laurence Brugieres; Léa Guerrini-Rous...; Chrystelle Colas; Martine Muleris; Neil A.J. Ryan; D. Gareth Evans; Hannah Grice; Emily Jessop; Annabel Kunzemann...; Lilla Marshall; Esther Schamschula; Klaus Oberhuber; Amedeo A. Azizi; Hagit Baris Feldman; Andreas Beilken; Nina Brauer; Triantafyllia Brozou; Karin Dahan; Ugur Demirsoy; Benoît Florkin; William Foulkes; Danuta Januszkiew...; Kristi J. Jones; Christian P. Kratz; Stephan Lobitz; Julia Meade; Michaela Nathrath; Hans-Jürgen Pander; Claudia Perne; Iman Ragab; Tim Ripperger; Thorsten Rosenbaum; Daniel Rueda; Tomasz Sarosiek; Astrid Sehested; Isabel Spier; Manon Suerink; Stefanie-Yvonne Z...; Johannes Zschocke; Gillian M. Borthwick; Katharina Wimmer; John Burn; Michael S. Jackson; Mauro Santibanez-...
• Keywords: Microsatellite Instability; Lynch Syndrome; MSH6; MSH2; Amplicon

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