TY - JOUR T1 - High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers JF - Journal of Medical Genetics JO - J Med Genet SP - 269 LP - 273 DO - 10.1136/jmedgenet-2019-106272 VL - 57 IS - 4 AU - Maribel González-Acosta AU - Fátima Marín AU - Benjamin Puliafito AU - Nuria Bonifaci AU - Anna Fernández AU - Matilde Navarro AU - Hector Salvador AU - Francesc Balaguer AU - Silvia Iglesias AU - Angela Velasco AU - Elia Grau Garces AU - Victor Moreno AU - Luis Ignacio Gonzalez-Granado AU - Pilar Guerra-García AU - Rosa Ayala AU - Benoît Florkin AU - Christian Kratz AU - Tim Ripperger AU - Thorsten Rosenbaum AU - Danuta Januszkiewicz-Lewandowska AU - Amedeo A Azizi AU - Iman Ragab AU - Michaela Nathrath AU - Hans-Jürgen Pander AU - Stephan Lobitz AU - Manon Suerink AU - Karin Dahan AU - Thomas Imschweiler AU - Ugur Demirsoy AU - Joan Brunet AU - Conxi Lázaro AU - Daniel Rueda AU - Katharina Wimmer AU - Gabriel Capellá AU - Marta Pineda Y1 - 2020/04/01 UR - http://jmg.bmj.com/content/57/4/269.abstract N2 - 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. ER -