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      Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 2 , 10 , 11 , 12 , 13 , 14 , 4 , 15 , 16 , 17 , 18 , 19 , 20 , 7 , 21 , 22 , 23 , 24 , 12 , 20 , 25 , 26 , 27 , 28 , 4 , 24 , 29 , (the Mallorca group)
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      BMJ Publishing Group
      Hnpcc Syndrome, Gastrointestinal Cancer, Colorectal Cancer Genes, Colorectal Carcinoma, Cancer Genetics

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          Abstract

          Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

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          Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.

          Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.
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            Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

            Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.
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              Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).

              Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome. Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not. Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                June 2013
                13 February 2013
                : 62
                : 6
                : 812-823
                Affiliations
                [1 ]Department of Gastroenterology, Leiden University Medical Centre , Leiden, The Netherlands
                [2 ]Hereditary Cancer Program, Catalan Institute of Oncology , Barcelona, Spain
                [3 ]Department of Medical Genetics Haartman Institute Biomedicum, University of Helsinki , Helsinki, Finland
                [4 ]Department of Clinical Genetics, Leiden University Medical Centre , Leiden, The Netherlands
                [5 ]Department of Medical Genetics, Complejo Hospitalario de Navarre , Pamplona, Spain
                [6 ]Institute of Human Genetics, University Hospital , Bonn, Germany
                [7 ]The Danish HNPCC-Register, Department of Gastroenterology and Clinical Research Center, Copenhagen University Hospital, Hvidovre, Denmark
                [8 ]Department of Surgery, Hospital Tumori , Milan, Italy
                [9 ]Institute of Human Genetics , Newcastle upon Tyne, UK
                [10 ]Department of Genetics, Hospital Pitié-Salpêtrière AP.HP , Paris, France
                [11 ]Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig, Germany
                [12 ]Institute of Medical Genetics, Cardiff University and Universitiy Hospital of Wales , Cardiff, UK
                [13 ]Department of Clinical Pathophysiology, University of Florence, and Tuscan Tumor Institute , Florence, Italy
                [14 ]Division of Medical Genetics and Department of Biomedicine, University of Children's Hospital , Basel, Switzerland
                [15 ]Department of Clinical Genetics, St George's University of London Hospital , London, UK
                [16 ]Department of Gastroenterology, Konstantopoulio University Hospital , Athens, Greece
                [17 ]Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Scientist Centre , Manchester, UK
                [18 ]Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm, Sweden
                [19 ]Department of Surgery, Jyvaskyla Central Hospital, Jyvaskyla & Institute of Clinical Medicine, University of Eastern Finland , Kuopio, Finland
                [20 ]Department of Medical Genetics, The Norwegian Radium Hospital University Hospital , Oslo, Norway
                [21 ]Department of Gastroenterology, University Medical Centre Radboud , Nijmegen, The Netherlands
                [22 ]Department of Digestive Surgery, Hospital Saint-Antoine, University Pierre et Marie , Paris, France
                [23 ]Department of Internal Medicine, Universtiy Hospital , Modena, Italy
                [24 ]Department of Surgery, Helsinki University Central Hospital , Helsinki, Finland
                [25 ]Department of Genetics, University of Groningen, University Medical Centre Groningen , Groningen, The Netherlands
                [26 ]Digestive Oncology Unit, Department of Internal Medicine, University Hospital Gasthuisberg , Leuven, Belgium.
                [27 ]Family Cancer Clinics, St Mark's Hospital, CRUK Cancer Centre, Imperial College London , Harrow, UK
                [28 ]Medical Faculty, Institute of Human Genetics, University of Duesseldorf , Duesseldorf, Germany
                [29 ]Department of Surgery, HELIOS St Josefs Hospital Bochum-Linden (Helios) , Bochum, Germany
                Author notes
                [Correspondence to ] Professor Dr Hans F A Vasen, Dutch Hereditary Cancer Registry & Department of Gastroenterology, Leiden University Medical Centre, Rijnsburgerweg 10, Leiden 2333 AA, The Netherlands; hfavasen@ 123456stoet.nl
                Article
                gutjnl-2012-304356
                10.1136/gutjnl-2012-304356
                3647358
                23408351
                fb915d56-f919-4ddc-acc2-d0f216a9a3e9
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

                History
                : 17 December 2012
                : 15 January 2013
                : 16 January 2013
                Categories
                1506
                1507
                Guidelines
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                Gastroenterology & Hepatology
                hnpcc syndrome,gastrointestinal cancer,colorectal cancer genes,colorectal carcinoma,cancer genetics

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