Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Mev Dominguez-Valentin, Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. mev.dominguez.valentin@rr-research.no.
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  • Julian R Sampson, Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK. sampson@cardiff.ac.uk.
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  • Toni T Seppälä, Clinicum, University of Helsinki, Helsinki, Finland. toni.seppala@fimnet.fi.
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  • Sanne W Ten Broeke, Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands.
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  • John-Paul Plazzer, Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia Department of Medicine, Melbourne University, Melbourne, Australia.
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  • Sigve Nakken, Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
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  • Christoph Engel, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
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  • Stefan Aretz, s Institute of Human Genetics , University of Bonn , Bonn , Germany.
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  • Mark A Jenkins, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
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  • Lone Sunde
  • Inge Bernstein, Aalborg University
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  • Gabriel Capella, Hereditary Cancer Program, Institut Catal. d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
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  • Francesc Balaguer, Gastroenterology Department, Hospital Clinic 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, Barcelona, Spain.
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  • Huw Thomas, St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK.
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  • D Gareth Evans, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
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  • John Burn, Institute for Genetic Medicine, Newcastle University, Newcastle-upon-Tyne
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  • Marc Greenblatt, Department of Surgery, The Robert Larner, M.D. College of Medicine at The University of Vermont, Burlington, Vermont, USA.
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  • Eivind Hovig, Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway Department of Informatics, University of Oslo, Oslo, Norway.
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  • Wouter H de Vos Tot Nederveen Cappel, Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
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  • Rolf H Sijmons, Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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  • Lucio Bertario, Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
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  • Maria Grazia Tibiletti, Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell'Insubria, Varese, Italy.
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  • Giulia Martina Cavestro, Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy.
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  • Annika Lindblom, Department of Molecular Medicine and Surgery and Department of Clinical Genetics, Karolinska Institutet and University Hospital, Stockholm, Sweden.
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  • Adriana Della Valle, Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
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  • Francisco Lopez-Köstner, Lab. Oncología y Genética Molecular, Unidad de coloproctología, Clínica Las Condes, Santiago, Chile.
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  • Nathan Gluck, Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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  • Lior H Katz, High Risk and GI Cancer prevention Clinic, Gastro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel.
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  • Karl Heinimann, Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
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  • Carlos A Vaccaro, Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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  • Reinhard Büttner, Institute of Pathology, University of Cologne, Cologne, Germany.
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  • Heike Görgens, Department of Surgical Research, Technische Universität Dresden, Dresden, Germany.
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  • Elke Holinski-Feder, Center of Medical Genetics, Munich, Germany.
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  • Monika Morak, Center of Medical Genetics, Munich, Germany.
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  • Stefanie Holzapfel, s Institute of Human Genetics , University of Bonn , Bonn , Germany.
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  • Robert Hüneburg, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; Department of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany.
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  • Magnus von Knebel Doeberitz, Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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  • Markus Loeffler, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
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  • Nils Rahner, Institute of Human Genetics, Medical School, Heinrich-Heine-University, Dusseldorf, Germany.
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  • Hans K Schackert, Department of Surgical Research, Technische Universität Dresden, Dresden, Germany.
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  • Verena Steinke-Lange, Center of Medical Genetics, Munich, Germany.
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  • Wolff Schmiegel, Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
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  • Deepak Vangala, Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
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  • Kirsi Pylvänäinen, Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
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  • Laura Renkonen-Sinisalo, Applied Tumour Genomics Research Program, University of Helsinki, Helsinki, Finland.
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  • John L Hopper, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
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  • Aung Ko Win, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
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  • Robert W Haile, Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA.
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  • Noralane M Lindor, Department of Health Science Research, Mayo Clinic Arizona, Phoenix, AZ, USA.
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  • Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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  • Loïc Le Marchand, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
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  • Polly A Newcomb, Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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  • Jane C Figueiredo, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
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  • Stephen N Thibodeau, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First StSW, Rochester, MN, 55905, USA.
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  • Karin Wadt, University of Copenhagen
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  • Christina Therkildsen, The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
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  • Henrik Okkels, Aalborg University
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  • Zohreh Ketabi, Department of Obstetrics and Gynaecology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen East, Denmark.
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  • Leticia Moreira, Gastroenterology Department, Hospital Clinic 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, Barcelona, Spain.
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  • Ariadna Sánchez, Gastroenterology Department, Hospital Clinic 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, Barcelona, Spain.
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  • Miquel Serra-Burriel, Universitat de Barcelona & Centre de Recerca en Economia i Salut (CRES-UPF), Barcelona, Spain.
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  • Marta Pineda, Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
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  • Matilde Navarro, Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
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  • Ignacio Blanco, Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
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  • Kate Green, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
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  • Fiona Lalloo, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
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  • Emma J Crosbie, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and St Mary's Hospital, Manchester, UK.
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  • James Hill, Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK.
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  • Oliver G Denton, Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, UK.
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  • Ian M Frayling, Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, UK.
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  • Einar Andreas Rødland, Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
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  • Hans Vasen, Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
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  • Miriam Mints, Department of Women's and Children's health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
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  • Florencia Neffa, Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
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  • Patricia Esperon, Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
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  • Karin Alvarez, Lab. Oncología y Genética Molecular, Unidad de coloproctología, Clínica Las Condes, Santiago, Chile.
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  • Revital Kariv, Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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  • Guy Rosner, Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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  • Tamara Alejandra Pinero, Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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  • María Laura Gonzalez, Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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  • Pablo Kalfayan, Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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  • Douglas Tjandra, Department of Medicine, University of Melbourne, Melbourne, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
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  • Ingrid M Winship, Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3010, Australia.
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  • Finlay Macrae, Department of Medicine, University of Melbourne, Melbourne, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.
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  • Gabriela Möslein, Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University of Witten-Hardecke, Wuppertal, Germany.
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  • Jukka-Pekka Mecklin, Departments of Surgery, University of Jyväskylä and Central Finland Central Hospital, Jyväskylä, Finland.
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  • Maartje Nielsen, Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands.
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  • Pål Møller, Centre for Cancer Cell Reprogamming, University of Oslo, Oslo, Norway.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Original languageEnglish
JournalGenetics in Medicine
Volume22
Issue1
Pages (from-to)15-25
Number of pages11
ISSN1098-3600
DOIs
Publication statusPublished - Jan 2020

    Research areas

  • Lynch syndrome, MLH1, MSH2, MSH6, PMS2

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