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Title:

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

Document type:
Article; Journal Article; Research Support, Non-U.S. Gov't
Author(s):
Gallon, Richard; Phelps, Rachel; Hayes, Christine; Brugieres, Laurence; Guerrini-Rousseau, Léa; Colas, Chrystelle; Muleris, Martine; Ryan, Neil A J; Evans, D Gareth; Grice, Hannah; Jessop, Emily; Kunzemann-Martinez, Annabel; Marshall, Lilla; Schamschula, Esther; Oberhuber, Klaus; Azizi, Amedeo A; Baris Feldman, Hagit; Beilken, Andreas; Brauer, Nina; Brozou, Triantafyllia; Dahan, Karin; Demirsoy, Ugur; Florkin, Benoît; Foulkes, William; Januszkiewicz-Lewandowska, Danuta; Jones, Kristi J; Kratz, C...     »
Abstract:
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.
Journal title abbreviation:
Gastroenterology
Year:
2023
Journal volume:
164
Journal issue:
4
Pages contribution:
579-592.e8
Fulltext / DOI:
doi:10.1053/j.gastro.2022.12.017
Pubmed ID:
http://view.ncbi.nlm.nih.gov/pubmed/36586540
Print-ISSN:
0016-5085
TUM Institution:
1310; Klinik und Poliklinik für Kinder- und Jugendmedizin (Prof. Hauer)
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