Hereditary Cancer in Clinical Practice (Oct 2023)
Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
- Pal Møller,
- Toni T. Seppälä,
- Aysel Ahadova,
- Emma J. Crosbie,
- Elke Holinski-Feder,
- Rodney Scott,
- Saskia Haupt,
- Gabriela Möslein,
- Ingrid Winship,
- Sanne W. Bajwa-ten Broeke,
- Kelly E. Kohut,
- Neil Ryan,
- Peter Bauerfeind,
- Laura E. Thomas,
- D. Gareth Evans,
- Stefan Aretz,
- Rolf H. Sijmons,
- Elizabeth Half,
- Karl Heinimann,
- Karoline Horisberger,
- Kevin Monahan,
- Christoph Engel,
- Giulia Martina Cavestro,
- Robert Fruscio,
- Naim Abu-Freha,
- Levi Zohar,
- Luigi Laghi,
- Lucio Bertario,
- Bernardo Bonanni,
- Maria Grazia Tibiletti,
- Leonardo S. Lino-Silva,
- Carlos Vaccaro,
- Adriana Della Valle,
- Benedito Mauro Rossi,
- Leandro Apolinário da Silva,
- Ivana Lucia de Oliveira Nascimento,
- Norma Teresa Rossi,
- Tadeusz Dębniak,
- Jukka-Pekka Mecklin,
- Inge Bernstein,
- Annika Lindblom,
- Lone Sunde,
- Sigve Nakken,
- Vincent Heuveline,
- John Burn,
- Eivind Hovig,
- Matthias Kloor,
- Julian R. Sampson,
- Mev Dominguez-Valentin,
- On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org)
Affiliations
- Pal Møller
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital
- Toni T. Seppälä
- Faculty of Medicine and Health Technology, Cancer Centre, Tampere University and Tays, Tampere University Hospital
- Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital
- Emma J. Crosbie
- Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust
- Elke Holinski-Feder
- Medizinische Klinik Und Poliklinik IV, Klinikum Der Universität München
- Rodney Scott
- Hunter Medical Research Institute, University of Newcastle
- Saskia Haupt
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University
- Gabriela Möslein
- Surgical Center for Hereditary Tumors, Academic Hospital University
- Ingrid Winship
- Genomic Medicine, The Royal Melbourne Hospital
- Sanne W. Bajwa-ten Broeke
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Kelly E. Kohut
- Centre for Psychosocial Research in Cancer, Health Sciences, University of Southampton
- Neil Ryan
- Medical School, University of Edinburgh
- Peter Bauerfeind
- Hirslanden clinic
- Laura E. Thomas
- Institute of Life Science, Swansea University
- D. Gareth Evans
- Manchester Centre for Genomic Medicine, Division of Evolution Infection and Genomic Sciences, University of Manchester
- Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn
- Rolf H. Sijmons
- Department of Genetics, University of Groningen, University Medical Center Groningen
- Elizabeth Half
- Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus
- Karl Heinimann
- Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel
- Karoline Horisberger
- Department of General, Visceral and Transplatation Surgery, University Hospital of Mainz
- Kevin Monahan
- Lynch Syndrome & Family Cancer Clinic, Centre for Familial Intestinal Cancer, St Mark’s Hospital
- Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
- Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University
- Robert Fruscio
- Clinic of Obstetrics and Gynecology, Department of Medicine and Surgery, University of Milan-Bicocca, Fondazione IRCCS San Gerardo
- Naim Abu-Freha
- Soroka University Medical Center, Ben-Gurion University of the Negev
- Levi Zohar
- Service High Risk GI Cancer Gastroenterology, Department Rabin Medical Center
- Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital
- Lucio Bertario
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, IRCCS
- Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS
- Maria Grazia Tibiletti
- Ospedale di Circolo ASST Settelaghi, Università dell’Insubria
- Leonardo S. Lino-Silva
- Surgical Pathology, Instituto Nacional de Cancerologia
- Carlos Vaccaro
- Instituo Medicina Translacional e Ingenieria Biomedica - Hospital Italiano Bs As. - CONICET
- Adriana Della Valle
- Hospital Central de las Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU)
- Benedito Mauro Rossi
- Hospital Sírio-Libanês
- Leandro Apolinário da Silva
- Hospital Universitário Oswaldo Cruz/Universidade de Pernambuco
- Ivana Lucia de Oliveira Nascimento
- Instituto de Ciência da Saúde da UFBA/NOB-Grupo Oncoclinicas
- Norma Teresa Rossi
- Fundación para el Progreso de la Medicina y Sanatorio Allende
- Tadeusz Dębniak
- Department of Genetics and Pathology, Pomeranian Medical University
- Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä
- Inge Bernstein
- Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University
- Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet
- Lone Sunde
- Department of Clinical Genetics, Aalborg University Hospital
- Sigve Nakken
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital
- Vincent Heuveline
- Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University
- John Burn
- Faculty of Medical Sciences, Newcastle University
- Eivind Hovig
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital
- Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital
- Julian R. Sampson
- Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine
- Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, Oslo University Hospital
- On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org)
- DOI
- https://doi.org/10.1186/s13053-023-00263-3
- Journal volume & issue
-
Vol. 21,
no. 1
pp. 1 – 12
Abstract
Abstract The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
