Journal of Clinical Medicine (Jun 2021)
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in <i>MLH1</i> and <i>MSH2</i>: A Prospective Lynch Syndrome Database Study
- Mev Dominguez-Valentin,
- John-Paul Plazzer,
- Julian R. Sampson,
- Christoph Engel,
- Stefan Aretz,
- Mark A. Jenkins,
- Lone Sunde,
- Inge Bernstein,
- Gabriel Capella,
- Francesc Balaguer,
- Finlay Macrae,
- Ingrid M. Winship,
- Huw Thomas,
- Dafydd Gareth Evans,
- John Burn,
- Marc Greenblatt,
- Wouter H. de Vos tot Nederveen Cappel,
- Rolf H. Sijmons,
- Maartje Nielsen,
- Lucio Bertario,
- Bernardo Bonanni,
- Maria Grazia Tibiletti,
- Giulia Martina Cavestro,
- Annika Lindblom,
- Adriana Della Valle,
- Francisco Lopez-Kostner,
- Karin Alvarez,
- Nathan Gluck,
- Lior Katz,
- Karl Heinimann,
- Carlos A. Vaccaro,
- Sigve Nakken,
- Eivind Hovig,
- Kate Green,
- Fiona Lalloo,
- James Hill,
- Hans F. A. Vasen,
- Claudia Perne,
- Reinhard Büttner,
- Heike Görgens,
- Elke Holinski-Feder,
- Monika Morak,
- Stefanie Holzapfel,
- Robert Hüneburg,
- Magnus von Knebel Doeberitz,
- Markus Loeffler,
- Nils Rahner,
- Jürgen Weitz,
- Verena Steinke-Lange,
- Wolff Schmiegel,
- Deepak Vangala,
- Emma J. Crosbie,
- Marta Pineda,
- Matilde Navarro,
- Joan Brunet,
- Leticia Moreira,
- Ariadna Sánchez,
- Miquel Serra-Burriel,
- Miriam Mints,
- Revital Kariv,
- Guy Rosner,
- Tamara Alejandra Piñero,
- Walter Hernán Pavicic,
- Pablo Kalfayan,
- Sanne W. ten Broeke,
- Jukka-Pekka Mecklin,
- Kirsi Pylvänäinen,
- Laura Renkonen-Sinisalo,
- Anna Lepistö,
- Päivi Peltomäki,
- John L. Hopper,
- Aung Ko Win,
- Daniel D. Buchanan,
- Noralane M. Lindor,
- Steven Gallinger,
- Loïc Le Marchand,
- Polly A. Newcomb,
- Jane C. Figueiredo,
- Stephen N. Thibodeau,
- Christina Therkildsen,
- Thomas V. O. Hansen,
- Lars Lindberg,
- Einar Andreas Rødland,
- Florencia Neffa,
- Patricia Esperon,
- Douglas Tjandra,
- Gabriela Möslein,
- Toni T. Seppälä,
- Pål Møller
Affiliations
- Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
- John-Paul Plazzer
- The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK
- Julian R. Sampson
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Christoph Engel
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Stefan Aretz
- Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
- Mark A. Jenkins
- Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC 3010, Australia
- Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital, 9000 Aalborg, Denmark
- Inge Bernstein
- Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9100 Aalborg, Denmark
- Gabriel Capella
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Francesc Balaguer
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
- Finlay Macrae
- The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK
- Ingrid M. Winship
- Department of Genomic Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3052, Australia
- Huw Thomas
- Department of Surgery and Cancer, St Mark’s Hospital, Imperial College London, London HA1 3UJ, UK
- Dafydd Gareth Evans
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
- John Burn
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Marc Greenblatt
- Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
- Wouter H. de Vos tot Nederveen Cappel
- Department of Gastroenterology and Hepatology, Isala Clinics, 8015 Zwolle, The Netherlands
- Rolf H. Sijmons
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Maartje Nielsen
- Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC Leiden, The Netherlands
- Lucio Bertario
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, IRCCS, 20141 Milan, Italy
- Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
- Maria Grazia Tibiletti
- Ospedale di Circolo ASST Settelaghi, Centro di Ricerca Tumori Eredo-Familiari, Università dell’Insubria, 21100 Varese, Italy
- Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
- Adriana Della Valle
- Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Hospital Fuerzas Armadas, Montevideo 11600, Uruguay
- Francisco Lopez-Kostner
- Programa Cáncer Heredo Familiar, Clínica Universidad de los Andes, Santiago 7550000, Chile
- Karin Alvarez
- Programa Cáncer Heredo Familiar, Clínica Universidad de los Andes, Santiago 7550000, Chile
- Nathan Gluck
- Department of Gastroenterology, Sackler Faculty of Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv 64259, Israel
- Lior Katz
- The Department of Gastroenterology, Gastro-Oncology Unit, High Risk and GI Cancer Prevention Clinic, Sheba Medical Center, Sheba 91120, Israel
- Karl Heinimann
- Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland
- Carlos A. Vaccaro
- Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
- Sigve Nakken
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
- Eivind Hovig
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
- Kate Green
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
- Fiona Lalloo
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
- James Hill
- Department of Surgery, Central Manchester University Hospitals NHS, Foundation Trust, University of Manchester, London M13 9WL, UK
- Hans F. A. Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, 2333 Leiden, The Netherlands
- Claudia Perne
- Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
- Reinhard Büttner
- Institute of Pathology, University of Cologne, 50937 Cologne, Germany
- Heike Görgens
- Department of Surgery, Technische Universität Dresden, 01062 Dresden, Germany
- Elke Holinski-Feder
- The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK
- Monika Morak
- Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
- Stefanie Holzapfel
- Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
- Robert Hüneburg
- Department of Internal Medicine, University Hospital Bonn, 53127 Bonn, Germany
- Magnus von Knebel Doeberitz
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Markus Loeffler
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany
- Nils Rahner
- Medical School, Institute of Human Genetics, Heinrich-Heine-University, 40225 Dusseldorf, Germany
- Jürgen Weitz
- Department of Surgery, Technische Universität Dresden, 01062 Dresden, Germany
- Verena Steinke-Lange
- Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
- Wolff Schmiegel
- Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, D-44789 Bochum, Germany
- Deepak Vangala
- Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, D-44789 Bochum, Germany
- Emma J. Crosbie
- Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK and Division of Cancer Sciences, University of Manchester, Manchester M20 4GJ, UK
- Marta Pineda
- Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Matilde Navarro
- Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Joan Brunet
- Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Leticia Moreira
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
- Ariadna Sánchez
- Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
- Miquel Serra-Burriel
- Centre de Recerca en Economia i Salut (CRES-UPF), Universitat de Barcelona, 08002 Barcelona, Spain
- Miriam Mints
- Division of Obstetrics and Gyneacology, Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Solna, 171 77 Stockholm, Sweden
- Revital Kariv
- Department of Gastroenterology, Sackler Faculty of Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv 64259, Israel
- Guy Rosner
- Department of Gastroenterology, Sackler Faculty of Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv 64259, Israel
- Tamara Alejandra Piñero
- Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
- Walter Hernán Pavicic
- Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
- Pablo Kalfayan
- Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
- Sanne W. ten Broeke
- Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC Leiden, The Netherlands
- Jukka-Pekka Mecklin
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Kirsi Pylvänäinen
- Department of Education and Science, Sport and Health Sciences, Central Finland Hospital Nova, University of Jyväskylä, FI-40014 Jyväskylä, Finland
- Laura Renkonen-Sinisalo
- Applied Tumour Genomics Research Program, University of Helsinki, 00014 Helsinki, Finland
- Anna Lepistö
- Applied Tumour Genomics Research Program, University of Helsinki, 00014 Helsinki, Finland
- Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland
- John L. Hopper
- Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC 3010, Australia
- Aung Ko Win
- Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC 3010, Australia
- Daniel D. Buchanan
- Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC 3010, Australia
- Noralane M. Lindor
- Department of Health Science Research, Mayo Clinic Arizona, Phoenix, AZ 85054, USA
- Steven Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
- Loïc Le Marchand
- Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
- Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
- Jane C. Figueiredo
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Stephen N. Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
- Christina Therkildsen
- The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, 2560 Hvidovre, Denmark
- Thomas V. O. Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
- Lars Lindberg
- Gastro Unit, Copenhagen University Hospital, 2560 Hvidovre, Denmark
- Einar Andreas Rødland
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
- Florencia Neffa
- Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Hospital Fuerzas Armadas, Montevideo 11600, Uruguay
- Patricia Esperon
- Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Hospital Fuerzas Armadas, Montevideo 11600, Uruguay
- Douglas Tjandra
- Department of Medicine, Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
- Gabriela Möslein
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Toni T. Seppälä
- European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
- Pål Møller
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
- DOI
- https://doi.org/10.3390/jcm10132856
- Journal volume & issue
-
Vol. 10,
no. 13
p. 2856
Abstract
Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
Keywords