Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency
Gastroenterology, vol. 164, pp. 579–592.e8
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.
Authors 47
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Richard Gallon corresponding
Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. Electronic address: richard.gallon@newcastle.ac.uk
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Université Paris-Saclay · Institut Gustave Roussy
Affiliation as printed
Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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Inserm · Université Paris-Saclay · Institut Gustave Roussy
Affiliation as printed
Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France; Team "Genomics and Oncogenesis of pediatric Brain Tumors," INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Team “Genomics and Oncogenesis of pediatric Brain Tumors,” INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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Inserm · Université Paris Cité · Institut Curie
Affiliation as printed
Département de Génétique, Institut Curie, Paris, France; INSERM U830, Université de Paris, Paris, France
Département de Génétique, Institut Curie, Paris, France
INSERM U830, Université de Paris, Paris, France
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Inserm · Sorbonne Université · Centre de Recherche Saint-Antoine
Affiliation as printed
Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France
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Edinburgh Royal Infirmary · University of Bristol
Affiliation as printed
The Academic Women's Health Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Department of Gynaecology Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK
Department of Gynaecology Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK
The Academic Women’s Health Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Affiliation as printed
Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK
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Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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University College London · Newcastle University
Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Centre for Inflammation and Tissue Repair, University College London, London, UK
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Centre for Inflammation and Tissue Repair, University College London, London, UK
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Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Innsbruck Medical University · Universität Innsbruck
Affiliation as printed
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Innsbruck Medical University · Universität Innsbruck
Affiliation as printed
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Affiliation as printed
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
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Tel Aviv University · Tel Aviv Sourasky Medical Center
Affiliation as printed
The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Pediatric Oncology, Helios-Klinikum, Krefeld, Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
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Institute of Pathology and Genetics
Affiliation as printed
Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
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Affiliation as printed
Department of Pediatric Oncology, Kocaeli University, Kocaeli, Turkey
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University of Liège · Centre hospitalier régional de la Citadelle
Affiliation as printed
Department of Pediatrics, Citadelle Hospital, University of Liège, Liège, Belgium
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McGill University Health Centre · Jewish General Hospital · Lady Davis Institute for Medical Research · McGill University
Affiliation as printed
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
Department of Human Genetics, McGill University, Montreal, Quebec, Canada
Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
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Poznan University of Medical Sciences
Affiliation as printed
Department of Pediatric Oncology, Hematology and Transplantation Medical University, Poznan, Poland
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The University of Sydney · Children's Hospital at Westmead · Westmead Hospital
Affiliation as printed
Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia; University of Sydney School of Medicine, Sydney, New South Wales, Australia
Department of Clinical Genetics, Western Sydney Genetics Program, Children’s Hospital at Westmead, Sydney, New South Wales, Australia
University of Sydney School of Medicine, Sydney, New South Wales, Australia
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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Gemeinschaftsklinikum Mittelrhein
Affiliation as printed
Gemeinschaftsklinikum Mittelrhein, Department of Pediatric Hematology and Oncology, Koblenz, Germany
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Affiliation as printed
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Klinikum Kassel · Technical University of Munich
Affiliation as printed
Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany; Department of Pediatrics, Pediatric Oncology Center, Technische Universität München, Munich, Germany
Department of Pediatrics, Pediatric Oncology Center, Technische Universität München, Munich, Germany
Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany
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Affiliation as printed
Institut für Klinische Genetik, Olgahospital, Stuttgart, Germany
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University of Bonn · University Hospital Bonn
Affiliation as printed
Institute of Human Genetics, Medical Faculty, University of Bonn and National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
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Affiliation as printed
Pediatrics Department, Hematology-Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Human Genetics, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
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Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre
Affiliation as printed
Hereditary Cancer Laboratory, University Hospital Doce de Octubre, i+12 Research Institute, Madrid, Spain
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Affiliation as printed
Department of Oncology, Luxmed Onkologia, Warsaw, Poland
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Copenhagen University Hospital · Rigshospitalet
Affiliation as printed
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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University of Bonn · University Hospital Bonn
Affiliation as printed
Institute of Human Genetics, Medical Faculty, University of Bonn and National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Pediatric Hematology and Oncology, Children's Hospital, University Hospital, Frankfurt, Germany
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Innsbruck Medical University · Universität Innsbruck
Affiliation as printed
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Innsbruck Medical University · Universität Innsbruck
Affiliation as printed
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
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Affiliation as printed
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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