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      Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research

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          Abstract

          25–30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

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          Mutation and cancer: statistical study of retinoblastoma.

          A Knudson (1971)
          Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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            Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

            Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.
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              Accounting for human polymorphisms predicted to affect protein function.

              A major interest in human genetics is to determine whether a nonsynonymous single-base nucleotide polymorphism (nsSNP) in a gene affects its protein product and, consequently, impacts the carrier's health. We used the SIFT (Sorting Intolerant From Tolerant) program to predict that 25% of 3084 nsSNPs from dbSNP, a public SNP database, would affect protein function. Some of the nsSNPs predicted to affect function were variants known to be associated with disease. Others were artifacts of SNP discovery. Two reports have indicated that there are thousands of damaging nsSNPs in an individual's human genome; we find the number is likely to be much lower.
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                Author and article information

                Journal
                J Med Genet
                jmg
                jmedgenet
                Journal of Medical Genetics
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0022-2593
                1468-6244
                30 June 2010
                July 2010
                30 June 2010
                : 47
                : 7
                : 436-444
                Affiliations
                [1 ]MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK
                [2 ]Department Gastroenterology, Addenbrooke's Hospital, Cambridge, UK
                [3 ]Cambridge NIHR Biomedical Research Centre, University of Cambridge NHS Foundation Trust
                [4 ]Department Oesophago-Gastric Surgery, Addenbrooke's Hospital, Cambridge, UK
                [5 ]British Columbia Cancer Agency, Vancouver, Canada
                [6 ]Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of Porto/Hospital S. João, Porto, Portugal
                [7 ]Biochemistry Department, University of Otago, New Zealand
                [8 ]GI Cancer Genetics Clinic, Gastrointestinal Unit, Massachusetts General Hospital, Boston
                [9 ]Division of General Surgery, Stanford University, USA
                [10 ]Wolfson Digestive Diseases Centre, Queens Medical Centre, Nottingham University Hospitals NHS Trust
                [11 ]Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [12 ]Cancer Research UK Familial Gastric Cancer Study, University Department of Oncology, Addenbrooke's Hospital, Cambridge, UK
                [13 ]Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre
                Author notes
                Correspondence to Dr Rebecca Fitzgerald, MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK; rcf@ 123456hutchison-mrc.ac.uk

                These guidelines are the result of consensus statements agreed during the seventh workshop of the International Gastric Cancer Linkage Consortium (IGCLC) held on 20-21 November 2008 at the Cambridge Research Institute, Cambridge UK 2008

                Workshop participants: Mr William Allum, Consultant Upper GI Surgeon, Royal Marsden Hospital, London, UK; Mr Stephen Attwood, Consultant Upper GI and Laparoscopic Surgeon, Northumbria Healthcare Trust, UK; Dr Vanessa Blair, Surgical Research Fellow, University of Otago, New Zealand; Nicola Bradshaw, MacMillan Cancer Genetic Counsellor, Glasgow, UK; Dr Carole Brewer, Consultant in Clinical Genetics, Royal Devon & Exeter Hospital, UK; Prof. Carlos Caldas, Professor of Cancer Medicine, CR UK Cambridge Research Institute, UK; Prof. Fatima Carneiro, Professor of Pathology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of Porto/Hospital S. João, Porto, Portugal; Dr Annemieke Cats, Head of Department of Gastroenterology and Hepatology, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan, Amsterdam, The Netherlands; Dr Amanda Charlton, Hon. Senior Clinical Lecturer, Faculty Medical and Health Sciences, Imoversity of Auckland, New Zealand; Daniel C. Chung MD, Director, GI Cancer Genetics Clinic, Gastrointestinal Unit, Massachusetts General Hospital, Boston; Associate Professor in Medicine, Harvard Medical School, USA; Dr Trevor Cole, Geneticist, Birmingham Women's Hospital, Edgbaston, Birmingham, UK; Dr Gianni Corso, Department of General Surgery and Surgical Oncology, University of Siena, Italy; Prof. Jean Crabtree, Professor of Experimental Pathology, Leeds Institute Molecular Medicine, University of Leeds, UK; Dr Huw Dorkins, Consultant Clinical Geneticist, The Kennedy-Galton Centre, Harrow; UK; Sarah Downing, Genetic Counsellor, Addenbrooke's Hospital, Cambridge, UK; Dr Jason Dunn, Research Fellow, UCLH, London, UK; Sarah Dwerryhouse, Co-ordinator, Cancer Research UK Familial Gastric Cancer Study, UK; Dr Peter Fairclough, Consultant Gastroenterologist, Barts and The London NHS Trust, UK; Dr Rebecca Fitzgerald, Programme Leader & Hon. Consultant Gastroenterologist, Cambridge, UK; Dr James Going, Senior Lecturer, Pathology, Glasgow Royal Infirmary, UK; Samantha Grimes, Dietician, Addenbrooke's Hospital, Cambridge, UK; Prof. Parry Guilford, Associate Professor, Cancer Genetics Laboratory, University of Otago, New Zealand; Mr Mike Hallissey, Consultant in General Surgery, Queen Elizabeth Hospital, Birmingham, UK; Nina Hallowell PhD, Public Health Sciences, Pathology, University of Edinburgh, UK; Mr Richard Hardwick, Consultant Upper GI Surgeon, Cambridge, UK; Prof. Nicoline Hoogerbrugge, PI molecular basis of hereditary cancer, Associate Professor and Head of Hereditary Cancer Clinic, Radboud University Nijmegen Medical Centre, The Netherlands; Dr Laetitia Huiart, Department of Oncogenetics, Institut Paoli-Calmettes, Marseille, France; Prof. David Huntsman, British Columbia Cancer Agency, Vancouver, Canada; Dr Gisela Keller, Institute of Pathology, Munich, Germany; Dr Ann Kershaw, Consultant Genetic Counsellor, Addenbrooke's Hospital, Cambridge, UK; Dr Ajith Kumar, Consultant in Clinical Genetics, Great Ormond Street Hospital, London, UK; Dr Laurence Lovat, Consultant Gastroenterologist & Senior Lecturer in Laser Medicine, UCLH, London, UK; Professor Ken McColl, Head of Division of Gastroenterology, Gardiner Institute, Glasgow, UK; Dr Shane McKee, Consultant Clinical Geneticist, Belfast City Hospital, UK; Dr Jeffrey Norton, Professor of Surgery, Stanford University, USA; Dr Maria O'Donovan, Pathologist, Addenbrooke's Hospital, Cambridge, UK; Dr Carla Oliveira, Research Scientist, IPATIMUP, Portugal; Dr Sylvianne Olschwang, Geneticist, Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France and INSERM U891; Centre de Recherche en Cancérologie de Marseille, France; Mr Bijendra P Patel, Clinical Senior Lecturer and Consultant Upper GI Surgeon, Director of Surgical Skills Unit, Barts and The Royal London Hospital NHS Trust, UK; Dr Joan Paterson, Consultant, Clinical Genetics, Cambridge, UK; Dr Corrado Pedrazzani, Clinical-Research Senior Fellow in Surgical Oncology, Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena, Italy; Dr Paul Pharoah, Genetic Epidemiologist, Cambridge, UK; Dr Krish Ragunath, Associate Professor in Endoscopy, Wolfson Digestive Diseases Centre, Queens Medical Centre, Nottingham University Hospitals NHS Trust, UK; Dr Franco Roviello, Associate Professor of Surgery, Department of General Surgery and Surgical Oncology, University of Siena, Italy; Dr Vicki Save, Consultant Histopathologist, Royal Infirmary of Edinburgh, UK; Dr Siobhan Sengupta, Lecturer in Human Genetics, UCL Centre for Preimplantation Genetic Diagnosis, London, UK; Dr Raquel Seruca, Research Scientist, IPATIMUP, Portugal; Manish A. Shah MD, Medical Oncologist, Memorial Sloan Kettering Cancer Centre, New York, USA; Dr Hubert Stein, Professor of Surgery, Paracelsus Private Medical University, Salzburg, Austria; Dr Nicola Van Krieken, Pathologist, Amsterdam, The Netherlands; Prof.dr. J Han van Krieken, PI in Pathology, Radboud University Nijmegen Medical Centre, The Netherlands; Dr Matthew Wallis, Consultant Radiologist, Addenbrooke's Hospital, Cambridge, UK; Dr Debrah Wirtzfeld, Head, Surgical Oncology, CancerCare Manitoba, Associate Professor of Surgery, Oncology and Community Health Sciences, University of Manitoba, Canada. The workshop participants wish to thank Christine Fox for secretarial support and for all travel and accommodation arrangements.

                Article
                jmedgenet74237
                10.1136/jmg.2009.074237
                2991043
                20591882
                dd486313-c762-4fde-b4d3-c165f2fb331f
                © 2010, 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/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 19 October 2009
                : 7 December 2009
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                Genetics
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                Genetics
                gastroenterology, guidelines

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