Article (Scientific journals)
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.
Garcia-Pelaez, José; Barbosa-Matos, Rita; Lobo, Silvana et al.
2022In Lancet Oncology, 24 (1), p. 91-106
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Keywords :
Oncology
Abstract :
[en] ("[en] BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.","[en] ","")
Disciplines :
Genetics & genetic processes
Author, co-author :
Garcia-Pelaez, José;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Faculty of Medicine, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Barbosa-Matos, Rita;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Lobo, Silvana;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Dias, Alexandre;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Garrido, Luzia;  Centro Hospitalar Universitário São João, Porto, Portugal
Castedo, Sérgio;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Faculty of Medicine, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Centro Hospitalar Universitário São João, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal, European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal
Sousa, Sónia;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Pinheiro, Hugo;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Serviço de Medicina Interna, Centro Hospitalar Tâmega e Sousa, Penafiel, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Sousa, Liliana;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Escola de Economia e Gestão, Universidade do Minho, Braga, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Monteiro, Rita;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
Maqueda, Joaquin J;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Bioinf2Bio, Porto, Portugal
Fernandes, Susana;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
Carneiro, Fátima;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Faculty of Medicine, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Centro Hospitalar Universitário São João, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal, European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal
Pinto, Nádia;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Center of Mathematics, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Lemos, Carolina;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal, Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Pinto, Carla;  Department of Laboratory Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal
Teixeira, Manuel R;  Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal, Department of Laboratory Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal, European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal
Aretz, Stefan;  Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany, National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany, ERN GENTURIS, Bonn, Germany
Bajalica-Lagercrantz, Svetlana;  Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden, Cancer Theme, Karolinska University Hospital Solna, Stockholm, Sweden, ERN GENTURIS, Stockholm, Sweden
Balmaña, Judith;  Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain, ERN GENTURIS, Barcelona, Spain
Blatnik, Ana;  Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia, ERN GENTURIS, Ljubljana, Slovenia
Benusiglio, Patrick R;  Medical Genetics Department, Pitié-Salpêtrière Hospital, AP-HP and Sorbonne University, Paris, France
Blanluet, Maud;  Service de Génétique Oncologique, Institut Curie, Paris, France
Bours, Vincent ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics
Brems, Hilde;  Department of Human Genetics, University of Leuven, Leuven, Belgium
Brunet, Joan;  Hereditary Cancer Programme, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research and Girona Biomedical Research Institute, Barcelona-Girona, Spain, ERN GENTURIS, Barcelona, Spain
Calistri, Daniele;  Laboratorio di Bioscienze, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Capellá, Gabriel;  Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain, ERN GENTURIS, Barcelona, Spain
Carrera, Sergio;  Oncology Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain
Colas, Chrystelle;  Service de Génétique Oncologique, Institut Curie, Paris, France, ERN GENTURIS, Paris, France
Dahan, Karin;  Center of Human Genetics, IPG, Gosselies, Belgium
de Putter, Robin;  Clinical Genetics Department, University Hospital of Ghent, Ghent, Belgium, ERN GENTURIS, Ghent, Belgium
Desseignés, Camille;  Medical Genetics Department, Pitié-Salpêtrière Hospital, AP-HP and Sorbonne University, Paris, France
Domínguez-Garrido, Elena;  Molecular Diagnostics Laboratory, Fundación Rioja Salud, Logroño, Spain
Egas, Conceição;  CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Evans, D Gareth;  Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK, Manchester Centre for Genomic Medicine, Manchester, UK
Feret, Damien;  Center of Human Genetics, IPG, Gosselies, Belgium
Fewings, Eleanor;  Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
Fitzgerald, Rebecca C;  Early Cancer Institute, University of Cambridge, Cambridge, UK
Coulet, Florence;  Medical Genetics Department, Pitié-Salpêtrière Hospital, AP-HP and Sorbonne University, Paris, France
Garcia-Barcina, María;  Genetics Unit, Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain
Genuardi, Maurizio;  Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Salute Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy, UOC Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy, ERN GENTURIS, Rome, Italy
Golmard, Lisa;  Service de Génétique Oncologique, Institut Curie, Paris, France
Hackmann, Karl;  Institute for Clinical Genetics, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany, National Center for Tumor Diseases, Dresden, Germany: German Cancer Research Center, Heidelberg, Germany, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, German Cancer Consortium, Dresden, Germany
Hanson, Helen;  SouthWest Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK
Holinski-Feder, Elke;  Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany, Medizinisch Genetisches Zentrum, Munich, Germany, ERN GENTURIS, Munich, Germany
Hüneburg, Robert;  Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany, National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany, ERN GENTURIS, Bonn, Germany
Krajc, Mateja;  Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia, ERN GENTURIS, Ljubljana, Slovenia
Lagerstedt-Robinson, Kristina;  Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden, ERN GENTURIS, Stockholm, Sweden
Lázaro, Conxi;  Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain, ERN GENTURIS, Barcelona, Spain
Ligtenberg, Marjolijn J L;  Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands, Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands, ERN GENTURIS, Nijmegen, Netherlands
Martínez-Bouzas, Cristina;  Genetics Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain
Merino, Sonia;  Genetics Unit, Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain
Michils, Geneviève;  Department of Human Genetics, University of Leuven, Leuven, Belgium
Novaković, Srdjan;  Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia
Patiño-García, Ana;  Unidad de Medicina Genómica y Pediatría, Clínica Universidad de Navarra, Programa de Tumores Sólidos, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Navarra, Spain
Ranzani, Guglielmina Nadia;  Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
Schröck, Evelin;  Institute for Clinical Genetics, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany, National Center for Tumor Diseases, Dresden, Germany: German Cancer Research Center, Heidelberg, Germany, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, German Cancer Consortium, Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, ERN GENTURIS, Dresden, Germany
Silva, Inês;  GenoMed-Diagnósticos de Medicina Molecular, Lisbon, Portugal
Silveira, Catarina;  GenoMed-Diagnósticos de Medicina Molecular, Lisbon, Portugal
Soto, José L;  Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain
Spier, Isabel;  Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany, National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany, ERN GENTURIS, Bonn, Germany
Steinke-Lange, Verena;  Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany, Medizinisch Genetisches Zentrum, Munich, Germany, ERN GENTURIS, Munich, Germany
Tedaldi, Gianluca;  Laboratorio di Bioscienze, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Tejada, María-Isabel;  Genetics Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain
Woodward, Emma R;  Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK, Manchester Centre for Genomic Medicine, Manchester, UK
Tischkowitz, Marc;  Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
Hoogerbrugge, Nicoline;  Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands, ERN GENTURIS, Nijmegen, Netherlands
Oliveira, Carla;  Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal, Faculty of Medicine, University of Porto, Porto, Portugal, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal, Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal, European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal. Electronic address: carlaol@i3s.up.pt
More authors (59 more) Less
Language :
English
Title :
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.
Publication date :
24 November 2022
Journal title :
Lancet Oncology
ISSN :
1470-2045
eISSN :
1474-5488
Publisher :
Elsevier BV, England
Volume :
24
Issue :
1
Pages :
91-106
Peer reviewed :
Peer Reviewed verified by ORBi
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