[en] [en] 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.
Disciplines :
Genetics & genetic processes Pediatrics Oncology
Author, co-author :
Gallon, Richard ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. Electronic address: richard.gallon@newcastle.ac.uk
Phelps, Rachel; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Hayes, Christine; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Brugieres, Laurence; Department of Children and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Guerrini-Rousseau, Léa; 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
Colas, Chrystelle; Département de Génétique, Institut Curie, Paris, France, INSERM U830, Université de Paris, Paris, France
Muleris, Martine; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, Paris, France
Ryan, Neil A J; 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
Evans, D Gareth; Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK
Grice, Hannah; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Jessop, Emily; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Kunzemann-Martinez, Annabel; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK, Centre for Inflammation and Tissue Repair, University College London, London, UK
Marshall, Lilla; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Schamschula, Esther; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Oberhuber, Klaus; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Azizi, Amedeo A; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
Baris Feldman, Hagit; The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Beilken, Andreas; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Brozou, Triantafyllia; Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
Dahan, Karin; Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
Demirsoy, Ugur; Department of Pediatric Oncology, Kocaeli University, Kocaeli, Turkey
Foulkes, William; 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
Januszkiewicz-Lewandowska, Danuta; Department of Pediatric Oncology, Hematology and Transplantation Medical University, Poznan, Poland
Jones, Kristi J; 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
Kratz, Christian P; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Lobitz, Stephan; Gemeinschaftsklinikum Mittelrhein, Department of Pediatric Hematology and Oncology, Koblenz, Germany
Meade, Julia; Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Nathrath, Michaela; Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany, Department of Pediatrics, Pediatric Oncology Center, Technische Universität München, Munich, Germany
Pander, Hans-Jürgen; Institut für Klinische Genetik, Olgahospital, Stuttgart, Germany
Perne, Claudia; Institute of Human Genetics, Medical Faculty, University of Bonn and National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
Ragab, Iman; Pediatrics Department, Hematology-Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Ripperger, Tim; Department of Human Genetics, Hannover Medical School, Hannover, Germany
Rosenbaum, Thorsten; Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
Rueda, Daniel; Hereditary Cancer Laboratory, University Hospital Doce de Octubre, i+12 Research Institute, Madrid, Spain
Sarosiek, Tomasz; Department of Oncology, Luxmed Onkologia, Warsaw, Poland
Sehested, Astrid; Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Spier, Isabel; Institute of Human Genetics, Medical Faculty, University of Bonn and National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
Suerink, Manon; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Zimmermann, Stefanie-Yvonne; Department of Pediatric Hematology and Oncology, Children's Hospital, University Hospital, Frankfurt, Germany
Zschocke, Johannes; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Borthwick, Gillian M; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Wimmer, Katharina; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Burn, John; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Jackson, Michael S; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Santibanez-Koref, Mauro; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
The authors thank all of the patients and their families who provided samples for this study. The authors thank the Genomics Core Facility and Bioinformatics Support Unit, Newcastle University , Newcastle upon Tyne, United Kingdom, for their support of genome and amplicon sequencing, and genome sequence analysis, as well as the research group of Prof Joris Veltman, Newcastle University , Newcastle upon Tyne, United Kingdom, for providing a panel of control blood whole genome sequencing data for variant calling. The authors thank Cancer Research UK for their support through the Aspirin for Cancer Prevention (AsCaP) (C569/A24991) and CaPP (C1297/A15394) groups, and The Barbour Foundation (UK charity 328081). Collection of clinical data and biological samples for French patients was supported by la Fondation Gustave Roussy campaign: Guérir Le Cancer de l’Enfant au 21ème siècle. The study received nonfinancial support from the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) - Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021”. The authors thank the AsCaP steering committee members for their support: Prof Jack Cuzick, Queen Mary University of London (chair), Prof Frances Balkwill, Queen Mary University of London , Prof Tim Bishop, University of Leeds , Prof Sir John Burn, Newcastle University , Prof Andrew T. Chan, Harvard School of Medicine, Dr Colin Crooks, University of Nottingham, Prof Chris Hawkey, University of Nottingham, Prof Ruth Langley, University College London, Ms Mairead McKenzie, Independent Cancer Patients’ Voice, Dr Belinda Nedjai, Queen Mary University of London, Prof Paola Patrignani, Università G. d'Annunzio di Chieti-Pescara, Prof Carlo Patrono, Catholic University of the Sacred Heart, Rome, Dr Bianca Rocca, Catholic University of the Sacred Heart, Rome, and Dr Samuel Smith, University of Leeds. John Burn is a National Institute for Health and Care Research (NIHR) Senior Investigator and thanks the NIHR for their support. D. Gareth Evans is supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007).Funding This study was funded through the Aspirin for Cancer Prevention (AsCaP) group, Cancer Research UK Grant Code: C569/A24991. Cancer Research UK had no role in study design, analysis, or interpretation. The AsCaP group is led by its senior executive board: Prof J. Burn, Prof A. T. Chan, Prof J. Cuzick, Dr B. Nedjai, and Prof Ruth Langley.The authors thank all of the patients and their families who provided samples for this study. The authors thank the Genomics Core Facility and Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, United Kingdom, for their support of genome and amplicon sequencing, and genome sequence analysis, as well as the research group of Prof Joris Veltman, Newcastle University, Newcastle upon Tyne, United Kingdom, for providing a panel of control blood whole genome sequencing data for variant calling. The authors thank Cancer Research UK for their support through the Aspirin for Cancer Prevention (AsCaP) (C569/A24991) and CaPP (C1297/A15394) groups, and The Barbour Foundation (UK charity 328081). Collection of clinical data and biological samples for French patients was supported by la Fondation Gustave Roussy campaign: Guérir Le Cancer de l'Enfant au 21ème siècle. The study received nonfinancial support from the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) - Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021”. The authors thank the AsCaP steering committee members for their support: Prof Jack Cuzick, Queen Mary University of London (chair), Prof Frances Balkwill, Queen Mary University of London, Prof Tim Bishop, University of Leeds, Prof Sir John Burn, Newcastle University, Prof Andrew T. Chan, Harvard School of Medicine, Dr Colin Crooks, University of Nottingham, Prof Chris Hawkey, University of Nottingham, Prof Ruth Langley, University College London, Ms Mairead McKenzie, Independent Cancer Patients’ Voice, Dr Belinda Nedjai, Queen Mary University of London, Prof Paola Patrignani, Università G. d'Annunzio di Chieti-Pescara, Prof Carlo Patrono, Catholic University of the Sacred Heart, Rome, Dr Bianca Rocca, Catholic University of the Sacred Heart, Rome, and Dr Samuel Smith, University of Leeds. John Burn is a National Institute for Health and Care Research (NIHR) Senior Investigator and thanks the NIHR for their support. D. Gareth Evans is supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). Genome sequence BAM and amplicon sequence FASTQ files are available from the European Nucleotide Archive (https://www.ebi.ac.uk/ena/browser/home) using Study IDs PRJEB39601 and PRJEB53321, respectively. Richard Gallon, PhD (Conceptualization: Equal; Data curation: Lead; Formal analysis: Equal; Funding acquisition: Supporting; Investigation: Equal; Methodology: Equal; Software: Equal; Supervision: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead). Rachel Phelps, MSc (Investigation: Supporting; Methodology: Supporting; Writing – review & editing: Supporting). Christine Hayes, BSc (Investigation: Supporting; Methodology: Supporting; Writing – review & editing: Supporting). Laurence Brugieres, MD (Data curation: Supporting; Resources: Equal; Writing – review & editing: Supporting). Léa Guerrini-Rousseau, MD (Data curation: Supporting; Resources: Equal; Writing – review & editing: Supporting). Chrystelle Colas, MD, PhD (Data curation: Supporting; Resources: Equal; Writing – review & editing: Supporting). Martine Muleris, HDR (Data curation: Supporting; Resources: Equal; Writing – review &editing: Supporting). Neil A. J. Ryan, MBChB, PhD (Resources: Equal; Writing – review & editing: Supporting). D. Gareth Evans, MD (Resources: Equal; Writing – review & editing: Supporting). Hannah Grice, BSc (Investigation: Supporting; Writing – review & editing: Supporting). Emily Jessop, BSc (Investigation: Supporting; Writing – review & editing: Supporting). Annabel Kunzemann-Martinez, MSc (Investigation: Supporting; Writing – review & editing: Supporting). Lilla Marshall, BSc (Investigation: Supporting; Writing – review & editing: Supporting). Esther Schamschula, PhD (Data curation: Supporting; Formal analysis: Supporting; Writing – review & editing: Supporting). Klaus Oberhuber, Dipl.MTA (Data curation: Supporting; Resources: Supporting; Writing– review & editing: Supporting). Amedeo A. Azizi, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Hagit Baris Feldman, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Andreas Beilken, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Nina Brauer, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Triantafyllia Brozou, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Karin Dahan, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Ugur Demirsoy, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Benoît Florkin, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). William Foulkes, MBBS, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Danuta Januszkiewicz-Lewandowska, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Kristi J. Jones, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Christian P. Kratz, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Stephan Lobitz, MD, MSc (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Julia Meade, MD (Data curation: Supporting; Resources: Supporting; Writing – review& editing: Supporting). Michaela Nathrath, MD (Data curation: Supporting; Resources: Supporting; Writing –review & editing: Supporting). Hans-Jürgen Pander, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Claudia Perne, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Iman Ragab, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Tim Ripperger, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Thorsten Rosenbaum, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Daniel Rueda, PhD (Data curation: Supporting; Resources: Supporting; Writing –review & editing: Supporting). Tomasz Sarosiek, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Astrid Sehested, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Isabel Spier, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Manon Suerink, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Stefanie-Yvonne Zimmermann, MD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Johannes Zschocke, MD, PhD (Data curation: Supporting; Resources: Supporting; Writing – review & editing: Supporting). Gillian M. Borthwick, PhD (Data curation: Supporting; Funding acquisition: Supporting; Project administration: Equal; Resources: Supporting; Writing – review & editing: Supporting). Katharina Wimmer, PhD (Data curation: Supporting; Formal analysis: Supporting; Resources: Equal; Supervision: Equal; Visualization: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting). John Burn, MD (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Supporting; Funding acquisition: Lead; Project administration: Supporting; Resources: Equal; Supervision: Equal; Visualization: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting). Michael S. Jackson, PhD (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Equal; Funding acquisition: Supporting; Investigation: Equal; Methodology: Equal; Project administration: Equal; Supervision: Equal; Visualization: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting). Mauro Santibanez-Koref, MD (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Equal; Funding acquisition: Supporting; Investigation: Equal; Methodology: Equal; Project administration: Equal; Software: Equal; Supervision: Equal; Visualization: Supporting; Writing – original draft: Supporting; Writing – review & editing: Supporting). Funding This study was funded through the Aspirin for Cancer Prevention (AsCaP) group, Cancer Research UK Grant Code: C569/A24991. Cancer Research UK had no role in study design, analysis, or interpretation. The AsCaP group is led by its senior executive board: Prof J. Burn, Prof A. T. Chan, Prof J. Cuzick, Dr B. Nedjai, and Prof Ruth Langley.
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