1 Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway 2 Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway 3 Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany 4 Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland 5 The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark 6 Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark 7 Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr, Germany 8 MGZ – Medizinisch Genetisches Zentrum, Munich, Germany 9 Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milano, Italy 10 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, London, UK 11 Manchester Centre for Genomic Medicine, University of Manchester, London, UK 12 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 13 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melborne, Australia 14 Department of Medicine, Melbourne University, Melborne, Australia 15 Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain 16 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 17 Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, UK 18 Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands 19 Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne, UK 20 Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway 21 Department of Informatics, University of Oslo, Olso, Norway 22 Department of Mathematics and Statistics, Lancaster University, Lancaster, UK 23 Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands 24 Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, London, UK 25 Department of Clinical Genetics and Department of Human Genetics Leiden, University Medical Centre, Leiden, The Netherlands 26 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia 27 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark 28 Department of Biomedicine, Aarhus University, Aarhus, Denmark 29 Department of Women’s and Children’s health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden 30 Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland 31 Department of Education and Science, Central Finland Health Care District, yväskylä, Finland 32 Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy 33 University of Eastern Finland, Kuopio, Finland 34 Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany
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BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website http://www.lscarisk.org to facilitate this.