High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers

Abstract

IntroductionLynch 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 methodsBlood 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.ResultsThe 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).ConclusionsThe 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.

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

“…The results of this approach also showed good correlations with the MSI assay presented by Richard Gallon. This work has been recently published by González-Acosta et al [8].…”

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

“…However, both small pool PCR and PCR combined with cloning are laborious or require specialist setups unsuited to diagnostic services. Recently, scalable NGS-based methods have been developed that detect low level MSI in the non-neoplastic PBLs of CMMRD patients [ 258 , 259 ], a signal that is not detectable by traditional FLA [ 260 ]. Both NGS-based methods were able to perfectly separate CMMRD from control PBLs, including CMMRD due to hypomorphic variants in PMS2 , but could not differentiate LS gene carrier from control PBLs [ 258 , 259 ].…”

“…Recently, scalable NGS-based methods have been developed that detect low level MSI in the non-neoplastic PBLs of CMMRD patients [ 258 , 259 ], a signal that is not detectable by traditional FLA [ 260 ]. Both NGS-based methods were able to perfectly separate CMMRD from control PBLs, including CMMRD due to hypomorphic variants in PMS2 , but could not differentiate LS gene carrier from control PBLs [ 258 , 259 ]. Together, these results suggest that only the most sensitive of methods can detect increased MSI in the non-neoplastic tissues of LS gene carriers, but the current methods available are unsuited to high throughput LS screening.…”

Wolbachia in Native Populations of Aedes albopictus (Diptera: Culicidae) From Yucatan Peninsula, Mexico

“…In Mexico, Ae. albopictus has been recorded in 16 states including Mexico City, Guanajuato, Jalisco, Coahuila, Chiapas, Hidalgo, Morelos, Nuevo León, Oaxaca, San Luis Potosí, Sinaloa, Tabasco, Tamaulipas, Veracruz, Yucatán, and Quintana Roo ( Villegas-Trejo et al 2010 , Salomón-Grajales et al 2012 , Ortega-Morales et al 2018 , Contreras-Perera et al 2019 , Dávalos-Becerril et al 2019 , González-Acosta et al 2020 ), but its geographical distribution is expected to increase because the macro- and micro ecological conditions suitable for its establishment, particularly throughout South Mexico ( Pech-May et al 2016 , Yañez-Arenas et al 2018 ).…”