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

Autor: Dominguez-Valentin M; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. mev.dominguez.valentin@rr-research.no., Sampson JR; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK. sampson@cardiff.ac.uk., Seppälä TT; Department of Gastrointestinal Surgery, Helsinki University Central Hospital, Helsinki, Finland. toni.seppala@fimnet.fi.; Clinicum, University of Helsinki, Helsinki, Finland. toni.seppala@fimnet.fi., Ten Broeke SW; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Plazzer JP; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia., Nakken S; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway., Engel C; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany., Aretz S; Institute of Human Genetics, University of Bonn, Bonn, Germany., Jenkins MA; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia., Sunde L; Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Bernstein I; Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark., Capella G; Hereditary Cancer Program, Institut Catal. d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Balaguer F; 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., Thomas H; St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK., Evans DG; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.; Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK., Burn J; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Greenblatt M; University of Vermont College of Medicine, Burlington, VT, USA., Hovig E; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.; Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway., de Vos Tot Nederveen Cappel WH; Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands., Sijmons RH; Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands., Bertario L; Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy., Tibiletti MG; Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell'Insubria, Varese, Italy., Cavestro GM; Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy., Lindblom A; Department of Molecular Medicine and Surgery and Department of Clinical Genetics, Karolinska Institutet and University Hospital, Stockholm, Sweden., Della Valle A; Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay., Lopez-Köstner F; Lab. Oncología y Genética Molecular, Unidad de coloproctología, Clínica Las Condes, Santiago, Chile., Gluck N; Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Katz LH; High Risk and GI Cancer prevention Clinic, Gastro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel., Heinimann K; Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland., Vaccaro CA; Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.; Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina., Büttner R; Institute of Pathology, University of Cologne, Cologne, Germany., Görgens H; Department of Surgical Research, Technische Universität Dresden, Dresden, Germany., Holinski-Feder E; Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.; Center of Medical Genetics, Munich, Germany., Morak M; Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.; Center of Medical Genetics, Munich, Germany., Holzapfel S; Institute of Human Genetics, University of Bonn, Bonn, Germany., Hüneburg R; Department of Internal Medicine, University Hospital Bonn, Bonn, Germany., Knebel Doeberitz MV; Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Loeffler M; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany., Rahner N; Institute of Human Genetics, Medical School, Heinrich-Heine-University, Dusseldorf, Germany., Schackert HK; Department of Surgical Research, Technische Universität Dresden, Dresden, Germany., Steinke-Lange V; Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.; Center of Medical Genetics, Munich, Germany., Schmiegel W; Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany., Vangala D; Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany., Pylvänäinen K; Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland., Renkonen-Sinisalo L; Department of Gastrointestinal Surgery, Helsinki University Central Hospital, Helsinki, Finland.; Applied Tumour Genomics Research Program, University of Helsinki, Helsinki, Finland., Hopper JL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia., Win AK; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia., Haile RW; Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA., Lindor NM; Department of Health Science Research, Mayo Clinic Arizona, Phoenix, AZ, USA., Gallinger S; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Le Marchand L; University of Hawaii Cancer Center, Honolulu, HI, USA., Newcomb PA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Figueiredo JC; Cedars-Sinai Medical Center, Los Angeles, CA, USA., Thibodeau SN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Wadt K; Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark., Therkildsen C; The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark., Okkels H; Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark., Ketabi Z; Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Rigshospitalet, Denmark., Moreira L; 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., Sánchez A; 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., Serra-Burriel M; Universitat de Barcelona & Centre de Recerca en Economia i Salut (CRES-UPF), Barcelona, Spain., Pineda M; Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Navarro M; Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Blanco I; Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Green K; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK., Lalloo F; Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK., Crosbie EJ; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and St Mary's Hospital, Manchester, UK., Hill J; Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK., Denton OG; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Frayling IM; Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK., Rødland EA; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway., Vasen H; Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands., Mints M; Department of Women's and Children's health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden., Neffa F; Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay., Esperon P; Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay., Alvarez K; Lab. Oncología y Genética Molecular, Unidad de coloproctología, Clínica Las Condes, Santiago, Chile., Kariv R; Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Rosner G; Department of Gastroenterology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Pinero TA; Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.; Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina., Gonzalez ML; Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina., Kalfayan P; Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina., Tjandra D; Department of Medicine, Melbourne University, Melbourne, Australia., Winship IM; Department of Medicine, Melbourne University, Melbourne, Australia.; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia., Macrae F; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.; Department of Medicine, Melbourne University, Melbourne, Australia., Möslein G; Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University of Witten-Hardecke, Wuppertal, Germany., Mecklin JP; Departments of Surgery, University of Jyväskylä and Central Finland Central Hospital, Jyväskylä, Finland., Nielsen M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Møller P; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.; Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.; Centre for Cancer Cell Reprogamming, University of Oslo, Oslo, Norway.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2020 Jan; Vol. 22 (1), pp. 15-25. Date of Electronic Publication: 2019 Jul 24.
DOI: 10.1038/s41436-019-0596-9
Abstrakt: 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.
Databáze: MEDLINE
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