High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers
Por:
González-Acosta M, Marín F, Puliafito B, Bonifaci N, Fernández A, Navarro M, Salvador-Hernandez H, Balaguer F, Iglesias S, Velasco A, Grau Garces E, Moreno V, Gonzalez-Granado LI, Guerra-García P, Ayala R, Florkin B, Kratz C, Ripperger T, Rosenbaum T, Januszkiewicz-Lewandowska D, Azizi AA, Ragab I, Nathrath M, Pander HJ, Lobitz S, Suerink M, Dahan K, Imschweiler T, Demirsoy U, Brunet J, Lázaro C, Rueda D, Wimmer K, Capellá G and Pineda M
Publicada:
1 abr 2020
Ahead of Print:
7 sep 2019
Resumen:
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.
Filiaciones:
González-Acosta M:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Marín F:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Puliafito B:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Bonifaci N:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Fernández A:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Navarro M:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Salvador-Hernandez H:
Pediatric Oncology Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
Balaguer F:
Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Iglesias S:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Velasco A:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Institut d'Investigació Biomèdica de Girona - IDIBGI, Girona, Spain
Grau Garces E:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Moreno V:
Cancer Prevention and Control Program, Catalan Institute of Oncology - ICO, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Gonzalez-Granado LI:
Immunodeficiencies Unit, Department of Pediatrics, Doce de Octubre University Hospital, i+12 Research Institute
Complutense University of Madrid, Madrid, Spain
Guerra-García P:
Hematology and Oncology Unit, Department of Pediatrics, Doce de Octubre University Hospital, Madrid, Spain
Ayala R:
Department of Hematology, Doce de Octubre University Hospital, i+12 Research Institute, Madrid, Spain
Florkin B:
University Department of Pediatrics, CHR Citadelle, Liege, Belgium
Kratz C:
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Ripperger T:
Department of Human Genetics, Hannover Medical School, Hannover, Germany
Rosenbaum T:
Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
Januszkiewicz-Lewandowska D:
Department of Pediatric Oncology, Hematology and Transplantation, Poznan University of Medical Sciences, Poznan, Poland
Azizi AA:
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
Ragab I:
Pediatrics Department, Hematology-Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Nathrath M:
Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany
Pediatric Oncology Center, Department of Pediatrics, Technische Universität München, Munchen, Germany
Pander HJ:
Institut für Klinische Genetik, Olgahospital, Stuttgart, Germany
Lobitz S:
Department of Pediatric Oncology/Pediatric Hematology, Kliniken der Stadt Köln gGmbH, Children's Hospital Amsterdamer Strasse, Koln, Germany
Suerink M:
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Dahan K:
Centre de Génétique Humaine, Institut de Pathologie et de Génétique (IPG), Gosselies, Belgium
Imschweiler T:
Pediatric Oncology, Helios-Klinikum, Krefeld, Germany
Demirsoy U:
Department of Pediatric Oncology, Kocaeli Universitesi, Kocaeli, Turkey
Brunet J:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Institut d'Investigació Biomèdica de Girona - IDIBGI, Girona, Spain
Lázaro C:
Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
Rueda D:
Hereditary Cancer Laboratory, Doce de Octubre University Hospital, i+12 Research Institute, Madrid, Spain
Wimmer K:
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
Green Published, hybrid
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