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Title: | High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers |
Author: | González Acosta, María Isabel Marín, Fátima Puliafito, Benjamin Bonifaci Cano, Núria Fernández, Anna Navarro, Matilde Salvador, Hector Balaguer Prunés, Francesc Iglesias, Silvia Velasco, Àngela Grau Garcés, Èlia Moreno Aguado, Víctor González Granado, Luis Ignacio Guerra García, Pilar Ayala, Rosa Florkin, Benoît Kratz, Christian Ripperger, Tim Rosenbaum, Thorsten Januszkiewicz-Lewandowska, Danuta Azizi, Amedeo A. Ragab, Iman Nathrath, Michaela Pander, Hans-Jürgen Lobitz, Stephan Suerink, Manon Dahan, Karin Imschweiler, thomas Demirsoy, Ugur Brunet, Joan Lázaro García, Conxi Rueda, Daniel Wimmer, Katharina Capellá, G. (Gabriel) Pineda, Marta |
Keywords: | Càncer colorectal Reparació de l'ADN Colorectal cancer DNA repair |
Issue Date: | 16-Jul-2020 |
Publisher: | BMJ Publishing Group |
Abstract: | Introduction: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Materials and methods: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. Results: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). Conclusions: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations. Keywords: constitutional mismatch repair deficiency; highly sensitive methodologies; lynch syndrome; microsatellite instability; next generation sequencing. |
Note: | Reproducció del document publicat a: https://doi.org/10.1136/jmedgenet-2019-106272 |
It is part of: | Journal of Medical Genetics, 2020, vol. 57, num. 4, p. 269-273 |
URI: | http://hdl.handle.net/2445/177396 |
Related resource: | https://doi.org/10.1136/jmedgenet-2019-106272 |
ISSN: | 0022-2593 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Ciències Clíniques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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