Authors and Affiliations:
José Garcia-Pelaez 1, Rita Barbosa-Matos 2, Silvana Lobo 2, Alexandre Dias 3, Luzia Garrido 4, Sérgio Castedo 5, Sónia Sousa 3, Hugo Pinheiro 6, Liliana Sousa 7, Rita Monteiro 8, Joaquin J Maqueda 9, Susana Fernandes 10, Fátima Carneiro 5, Nádia Pinto 11, Carolina Lemos 12, Carla Pinto 13, Manuel R Teixeira 14, Stefan Aretz 15, Svetlana Bajalica-Lagercrantz 16, Judith Balmaña 17, Ana Blatnik 18, Patrick R Benusiglio 19, Maud Blanluet 20, Vincent Bours 21, Hilde Brems 22, Joan Brunet 23, Daniele Calistri 24, Gabriel Capellá 25, Sergio Carrera 26, Chrystelle Colas 27, Karin Dahan 28, Robin de Putter 29, Camille Desseignés 19, Elena Domínguez-Garrido 30, Conceição Egas 31, D Gareth Evans 32, Damien Feret 28, Eleanor Fewings 33, Rebecca C Fitzgerald 34, Florence Coulet 19, María Garcia-Barcina 35, Maurizio Genuardi 36, Lisa Golmard 20, Karl Hackmann 37, Helen Hanson 38, Elke Holinski-Feder 39, Robert Hüneburg 40, Mateja Krajc 18, Kristina Lagerstedt-Robinson 41, Conxi Lázaro 25, Marjolijn J L Ligtenberg 42, Cristina Martínez-Bouzas 43, Sonia Merino 35, Geneviève Michils 22, Srdjan Novaković 44, Ana Patiño-García 45, Guglielmina Nadia Ranzani 46, Evelin Schröck 47, Inês Silva 48, Catarina Silveira 48, José L Soto 49, Isabel Spier 15, Verena Steinke-Lange 39, Gianluca Tedaldi 24, María-Isabel Tejada 43, Emma R Woodward 32, Marc Tischkowitz 33, Nicoline Hoogerbrugge 50, Carla Oliveira 51
1Instituto 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.
2Instituto 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.
3Instituto 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.
4Centro Hospitalar Universitário São João, Porto, Portugal.
5Instituto 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.
6Instituto 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.
7Instituto 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.
8Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
9Instituto 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.
10Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal.
11Instituto 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.
12Instituto 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.
13Department of Laboratory Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal.
14Institute 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.
15Institute 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.
16Department 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.
17Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain; ERN GENTURIS, Barcelona, Spain.
18Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia; ERN GENTURIS, Ljubljana, Slovenia.
19Medical Genetics Department, Pitié-Salpêtrière Hospital, AP-HP and Sorbonne University, Paris, France.
20Service de Génétique Oncologique, Institut Curie, Paris, France.
21Laboratory of Human Genetics, GIGA Institute, University of Liège, Liège, Belgium; Center of Genetics, University Hospital, Liège, Belgium; ERN GENTURIS, Liège, Belgium.
22Department of Human Genetics, University of Leuven, Leuven, Belgium.
23Hereditary Cancer Programme, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research and Girona Biomedical Research Institute, Barcelona-Girona, Spain; ERN GENTURIS, Barcelona, Spain.
24Laboratorio di Bioscienze, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
25Hereditary 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.
26Oncology Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain.
27Service de Génétique Oncologique, Institut Curie, Paris, France; ERN GENTURIS, Paris, France.
28Center of Human Genetics, IPG, Gosselies, Belgium.
29Clinical Genetics Department, University Hospital of Ghent, Ghent, Belgium; ERN GENTURIS, Ghent, Belgium.
30Molecular Diagnostics Laboratory, Fundación Rioja Salud, Logroño, Spain.
31CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
32Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, Manchester, UK.
33Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
34Early Cancer Institute, University of Cambridge, Cambridge, UK.
35Genetics Unit, Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain.
36Sezione 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.
37Institute 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.
38SouthWest Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
39Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; Medizinisch Genetisches Zentrum, Munich, Germany; ERN GENTURIS, Munich, Germany.
40Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; ERN GENTURIS, Bonn, Germany.
41Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden; ERN GENTURIS, Stockholm, Sweden.
42Department 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.
43Genetics Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain.
44Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
45Unidad 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.
46Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
47Institute 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.
48GenoMed-Diagnósticos de Medicina Molecular, Lisbon, Portugal.
49Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
50Department 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.
51Instituto 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
Abstract:
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).
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.
Journal: Lancet Oncology
Link: https://pubmed.ncbi.nlm.nih.gov/36436516/
