Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Mev Dominguez-Valentin¹, Saskia Haupt^{2

3}, Toni T Seppälä^{4

5

6}, Julian R Sampson⁷, Lone Sunde^{8

9}, Inge Bernstein^{10

11}, Mark A Jenkins¹², Christoph Engel¹³, Stefan Aretz¹⁴, Maartje Nielsen¹⁵, Gabriel Capella¹⁶, Francesc Balaguer¹⁷, Dafydd Gareth Evans¹⁸, John Burn¹⁹, Elke Holinski-Feder^{20

21}, Lucio Bertario²², Bernardo Bonanni²³, Annika Lindblom²⁴, Zohar Levi²⁵, Finlay Macrae^{26

27}, Ingrid Winship^{26

27

28}, John-Paul Plazzer^{26

27}, Rolf Sijmons²⁹, Luigi Laghi³⁰, Adriana Della Valle³¹, Karl Heinimann³², Tadeusz Dębniak³³, Robert Fruscio³⁴, Francisco Lopez-Koestner^{35

36}, Karin Alvarez-Valenzuela^{35

36}, Lior H Katz³⁷, Ido Laish³⁷, Elez Vainer³⁸, Carlos Vaccaro³⁹, Dirce Maria Carraro⁴⁰, Kevin Monahan⁴¹, Elizabeth Half⁴², Aine Stakelum⁴³, Des Winter⁴³, Rory Kennelly⁴³, Nathan Gluck⁴⁴, Harsh Sheth⁴⁵, Naim Abu-Freha⁴⁶, Marc Greenblatt⁴⁷, Benedito Mauro Rossi⁴⁸, Mabel Bohorquez⁴⁹, Giulia Martina Cavestro⁵⁰, Leonardo S Lino-Silva⁵¹, Karoline Horisberger^{52

53}, Maria Grazia Tibiletti⁵⁴, Ivana do Nascimento⁵⁵, Huw Thomas⁵⁶, Norma Teresa Rossi⁵⁷, Leandro Apolinário da Silva^{58

59}, Attila Zaránd⁶⁰, Juan Ruiz-Bañobre^{61

62}, Vincent Heuveline^{2

3}, Jukka-Pekka Mecklin^{63

64}, Kirsi Pylvänäinen⁶⁵, Laura Renkonen-Sinisalo^{5

6}, Anna Lepistö^{5

6}, Päivi Peltomäki⁶⁶, Christina Therkildsen⁶⁷, Mia Gebauer Madsen⁶⁸, Stefan Kobbelgaard Burgdorf⁶⁹, John L Hopper⁷⁰, Aung Ko Win⁷⁰, Robert W Haile⁷¹, Noralane Lindor⁷², Steven Gallinger⁷³, Loïc Le Marchand⁷⁴, Polly A Newcomb⁷⁵, Jane Figueiredo⁷⁵, Daniel D Buchanan^{76

77

78}, Stephen N Thibodeau⁷⁹, Magnus von Knebel Doeberitz^{80

81}, Markus Loeffler¹³, Nils Rahner⁸², Evelin Schröck^{83

84

85

86}, Verena Steinke-Lange^{87

88}, Wolff Schmiegel⁸⁹, Deepak Vangala⁸⁹, Claudia Perne¹⁴, Robert Hüneburg⁹⁰, Silke Redler⁸², Reinhard Büttner⁹¹, Jürgen Weitz⁹², Marta Pineda¹⁶, Nuria Duenas¹⁶, Joan Brunet Vidal¹⁶, Leticia Moreira¹⁷, Ariadna Sánchez¹⁷, Eivind Hovig^{1

93}, Sigve Nakken^{1

93

94}, Kate Green¹⁸, Fiona Lalloo¹⁸, James Hill⁹⁵, Emma Crosbie^{96

97}, Miriam Mints⁹⁸, Yael Goldberg⁹⁹, Douglas Tjandra^{26

27}, Sanne W Ten Broeke²⁹, Revital Kariv⁴³, Guy Rosner⁴³, Suresh H Advani¹⁰⁰, Lidiya Thomas¹⁰⁰, Pankaj Shah¹⁰¹, Mithun Shah¹⁰¹, Florencia Neffa³⁰, Patricia Esperon³⁰, Walter Pavicic¹⁰², Giovana Tardin Torrezan³⁹, Thiago Bassaneze⁴⁷, Claudia Alejandra Martin¹⁰³, Gabriela Moslein¹⁰⁴, Pål Moller¹

Affiliations

¹ Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379, Oslo, Norway.
² Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
³ Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
⁴ Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Finland.
⁵ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
⁶ Applied Tumor Genomics, Research Program Unit, University of Helsinki, Helsinki, Finland.
⁷ Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
⁸ Department of Clinical Genetics, Aalborg University Hospital, 9000, Aalborg, Denmark.
⁹ Department of Biomedicine, Aarhus University, DK-8000, Aarhus, Denmark.
¹⁰ Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark.
¹¹ Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark.
¹² Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, 3010, Victoria, Australia.
¹³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
¹⁴ Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany.
¹⁵ Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC, Leiden, the Netherlands.
¹⁶ Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L; Hospitalet de Llobregat, 08908, Barcelona, Spain.
¹⁷ 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, Barcelona, Spain.
¹⁸ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK.
¹⁹ Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
²⁰ Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336, Munich, Germany.
²¹ Center of Medical Genetics, 80335, Munich, Germany.
²² Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, IRCCS, 20141, Milan, Italy.
²³ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy.
²⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
²⁵ Service High Risk GI Cancer Gastroenterology, Department Rabin Medical Center, Israel.
²⁶ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.
²⁷ Department of Medicine, Melbourne University, Melbourne, Australia.
²⁸ Department of Medicine, University of Melbourne, Melbourne, Australia.
²⁹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³⁰ Department of Medicine and Surgery, Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, University of Parma, Parma, Italy.
³¹ Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
³² Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Switzerland.
³³ Department of Genetics and Pathology, International Hereditary Cancer Center, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland.
³⁴ Department of Medicine and Surgery, University of Milan Bicocca, A.O. San Gerardo, Clinic of Obstetrics and Gynecology, Via Pergolesi 33, Monza (MB), Italy.
³⁵ Clínica Universidad de los Andes, Chile.
³⁶ Programa Cáncer Heredo Familiar, Santiago, Chile.
³⁷ Department of Gastroenterology, Hadassah, Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
³⁸ Hadassah Medical Center, Israel.
³⁹ Hereditary Cancer Program (PROCANHE) Hospital Italiano de Buenos Aires, Argentina.
⁴⁰ Clinical and Functional Genomics Group, A.C.Camargo Cancer Center, Sao Paulo, Brazil.
⁴¹ Lynch Syndrome & Family Cancer Clinic, St Mark's Hospital, Harrow, HA1 3UJ, London, UK.
⁴² Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel.
⁴³ St Vincent's University Hospital, Ireland.
⁴⁴ Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
⁴⁵ Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics, FRIGE House, Ahmedabad, 380015, India.
⁴⁶ Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Southern Israel, Israel.
⁴⁷ University of Vermont, Larner College of Medicine, Burlington, VT, 05405, USA.
⁴⁸ Hospital Sirio Libanes, Sao Paulo, Brazil.
⁴⁹ University of Tolima, Tolima, Colombia.
⁵⁰ Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy.
⁵¹ Surgical Pathology, Instituto Nacional de Cancerologia, Mexico City, Mexico.
⁵² Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Switzerland.
⁵³ Depart-ment of Surgery, Universitätsmedizin Mainz, Germany.
⁵⁴ Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell'Insubria, Varese, Italy.
⁵⁵ Universidade Federal de Bahia, Bahia, Brazil.
⁵⁶ St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK.
⁵⁷ Fundación para el Progreso de la Medicina" y "Sanatorio Allende", Córdoba, Argentina.
⁵⁸ Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, Brazil.
⁵⁹ SEQUIPE, Recife, Brazil.
⁶⁰ 1st Department of Surgery, Semmelweis University, Hungary.
⁶¹ Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS); Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS); Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706, Santiago de Compostela, Spain.
⁶² Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain.
⁶³ Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁶⁴ Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland.
⁶⁵ Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
⁶⁶ Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
⁶⁷ The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶⁸ Department of Urology, Aarhus University Hospital, Denmark.
⁶⁹ Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark.
⁷⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
⁷¹ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, USA.
⁷² Department of Health Science Research, Mayo Clinic Arizona, USA.
⁷³ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Canada.
⁷⁴ University of Hawaii Cancer Center, USA.
⁷⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
⁷⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁷⁷ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
⁷⁸ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁷⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
⁸⁰ Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
⁸¹ Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸² Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
⁸³ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
⁸⁴ German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
⁸⁵ Institute for Clinical Genetics, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁸⁶ Hereditary Cancer Syndrome Center Dresden, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁸⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
⁸⁸ MGZ - Medical Genetics Center, Munich, Germany.
⁸⁹ Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
⁹⁰ Department of Internal Medicine, University Hospital Bonn, Bonn, Germany.
⁹¹ Institute of Pathology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁹² Technische Universität Dresden, Dresden, Germany.
⁹³ Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁹⁴ Centre for Cancer Cell Reprogramming (CanCell), Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁹⁵ Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, London, UK.
⁹⁶ Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK.
⁹⁷ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁹⁸ Division of Obstetrics and Gyneacology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
⁹⁹ Head Adult Genetic Service, Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
¹⁰⁰ Sushrut Hospital and Research Centre, Mumbai, India.
¹⁰¹ Zydus Cancer Centre, Ahmedabad, India.
¹⁰² Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, 94, Argentina.
¹⁰³ Hospital Privado Universiatrio de Córdoba, Cordoba, Argentina.
¹⁰⁴ Surgical Center for Hereditary Tumors, Ev. Bethesda Khs Duisburg, University Witten-Herdecke, Herdecke, Germany.

PMID: 37181409
PMCID: PMC10166779
DOI: 10.1016/j.eclinm.2023.101909

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Mev Dominguez-Valentin et al. EClinicalMedicine. 2023.

. 2023 Mar 20:58:101909.

doi: 10.1016/j.eclinm.2023.101909. eCollection 2023 Apr.

Authors

Affiliations

¹ Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379, Oslo, Norway.
² Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
³ Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
⁴ Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Finland.
⁵ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
⁶ Applied Tumor Genomics, Research Program Unit, University of Helsinki, Helsinki, Finland.
⁷ Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
⁸ Department of Clinical Genetics, Aalborg University Hospital, 9000, Aalborg, Denmark.
⁹ Department of Biomedicine, Aarhus University, DK-8000, Aarhus, Denmark.
¹⁰ Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark.
¹¹ Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark.
¹² Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, 3010, Victoria, Australia.
¹³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
¹⁴ Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany.
¹⁵ Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC, Leiden, the Netherlands.
¹⁶ Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L; Hospitalet de Llobregat, 08908, Barcelona, Spain.
¹⁷ 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, Barcelona, Spain.
¹⁸ Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK.
¹⁹ Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
²⁰ Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336, Munich, Germany.
²¹ Center of Medical Genetics, 80335, Munich, Germany.
²² Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, IRCCS, 20141, Milan, Italy.
²³ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy.
²⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
²⁵ Service High Risk GI Cancer Gastroenterology, Department Rabin Medical Center, Israel.
²⁶ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.
²⁷ Department of Medicine, Melbourne University, Melbourne, Australia.
²⁸ Department of Medicine, University of Melbourne, Melbourne, Australia.
²⁹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³⁰ Department of Medicine and Surgery, Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, University of Parma, Parma, Italy.
³¹ Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
³² Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Switzerland.
³³ Department of Genetics and Pathology, International Hereditary Cancer Center, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland.
³⁴ Department of Medicine and Surgery, University of Milan Bicocca, A.O. San Gerardo, Clinic of Obstetrics and Gynecology, Via Pergolesi 33, Monza (MB), Italy.
³⁵ Clínica Universidad de los Andes, Chile.
³⁶ Programa Cáncer Heredo Familiar, Santiago, Chile.
³⁷ Department of Gastroenterology, Hadassah, Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
³⁸ Hadassah Medical Center, Israel.
³⁹ Hereditary Cancer Program (PROCANHE) Hospital Italiano de Buenos Aires, Argentina.
⁴⁰ Clinical and Functional Genomics Group, A.C.Camargo Cancer Center, Sao Paulo, Brazil.
⁴¹ Lynch Syndrome & Family Cancer Clinic, St Mark's Hospital, Harrow, HA1 3UJ, London, UK.
⁴² Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel.
⁴³ St Vincent's University Hospital, Ireland.
⁴⁴ Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
⁴⁵ Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics, FRIGE House, Ahmedabad, 380015, India.
⁴⁶ Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Southern Israel, Israel.
⁴⁷ University of Vermont, Larner College of Medicine, Burlington, VT, 05405, USA.
⁴⁸ Hospital Sirio Libanes, Sao Paulo, Brazil.
⁴⁹ University of Tolima, Tolima, Colombia.
⁵⁰ Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy.
⁵¹ Surgical Pathology, Instituto Nacional de Cancerologia, Mexico City, Mexico.
⁵² Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Switzerland.
⁵³ Depart-ment of Surgery, Universitätsmedizin Mainz, Germany.
⁵⁴ Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell'Insubria, Varese, Italy.
⁵⁵ Universidade Federal de Bahia, Bahia, Brazil.
⁵⁶ St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK.
⁵⁷ Fundación para el Progreso de la Medicina" y "Sanatorio Allende", Córdoba, Argentina.
⁵⁸ Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, Brazil.
⁵⁹ SEQUIPE, Recife, Brazil.
⁶⁰ 1st Department of Surgery, Semmelweis University, Hungary.
⁶¹ Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS); Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS); Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706, Santiago de Compostela, Spain.
⁶² Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain.
⁶³ Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁶⁴ Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland.
⁶⁵ Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
⁶⁶ Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
⁶⁷ The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶⁸ Department of Urology, Aarhus University Hospital, Denmark.
⁶⁹ Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark.
⁷⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
⁷¹ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, USA.
⁷² Department of Health Science Research, Mayo Clinic Arizona, USA.
⁷³ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Canada.
⁷⁴ University of Hawaii Cancer Center, USA.
⁷⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
⁷⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁷⁷ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
⁷⁸ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁷⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
⁸⁰ Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
⁸¹ Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸² Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
⁸³ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
⁸⁴ German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
⁸⁵ Institute for Clinical Genetics, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁸⁶ Hereditary Cancer Syndrome Center Dresden, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁸⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
⁸⁸ MGZ - Medical Genetics Center, Munich, Germany.
⁸⁹ Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
⁹⁰ Department of Internal Medicine, University Hospital Bonn, Bonn, Germany.
⁹¹ Institute of Pathology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁹² Technische Universität Dresden, Dresden, Germany.
⁹³ Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁹⁴ Centre for Cancer Cell Reprogramming (CanCell), Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁹⁵ Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, London, UK.
⁹⁶ Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK.
⁹⁷ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁹⁸ Division of Obstetrics and Gyneacology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
⁹⁹ Head Adult Genetic Service, Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
¹⁰⁰ Sushrut Hospital and Research Centre, Mumbai, India.
¹⁰¹ Zydus Cancer Centre, Ahmedabad, India.
¹⁰² Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, 94, Argentina.
¹⁰³ Hospital Privado Universiatrio de Córdoba, Cordoba, Argentina.
¹⁰⁴ Surgical Center for Hereditary Tumors, Ev. Bethesda Khs Duisburg, University Witten-Herdecke, Herdecke, Germany.

PMID: 37181409
PMCID: PMC10166779
DOI: 10.1016/j.eclinm.2023.101909

Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.

Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.

Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.

Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome.

Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Keywords: Cancer risk; Lynch syndrome; MLH1; MSH2; MSH6; Mortality; PMS2; Prospective study; Survival.

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Conflict of interest statement

R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson.

Figures

**Fig. 1**
Crude survival (%) in *path_MLH1, path_MSH2, path_MSH6* and *path_PMS2* carriers subjected to colonoscopy surveillance after colon cancer diagnosed before age of 65 years. The dark line showed the survival probability, and the bars showed the 95% confidence interval for each *path_MMR* carrier: *path_MLH1* (orange), *path_MSH2* (green), *path_MSH6* (blue) and *path_PMS2* (purple). Categorization of carriers as dead or alive was made at last observation and was made for all carriers.

**Fig. 2**
Crude survival (%) in *path_MLH1, path_MSH2*, *path_MSH6* and *path_PMS2* carriers subjected to colonoscopy surveillance after endometrial cancer diagnosed before age of 65 years. The dark line showed the survival probability, and the bars showed the 95% confidence interval for each *path_MMR* carrier: *path_MLH1* (orange), *path_MSH2* (green), *path_MSH6* (blue) and *path_PMS2* (purple). Categorization of carriers as dead or alive was made at last observation and was made for all carriers.

See this image and copyright information in PMC

References

1. Ligtenberg M.J., Kuiper R.P., Chan T.L., et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009;41(1):112–117. - PubMed
1. Vasen H.F., Blanco I., Aktan-Collan K., et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812–823. - PMC - PubMed
1. Dominguez-Valentin M., Crosbie E.J., Engel C., et al. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report. Genet Med. 2021;23(4):705–712. - PMC - PubMed
1. Dominguez-Valentin M., Sampson J.R., Seppala T.T., et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2019;22(1):15–25. - PMC - PubMed
1. Seppala T., Pylvanainen K., Evans D.G., et al. Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report. Hered Cancer Clin Pract. 2017;15:18. - PMC - PubMed

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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

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