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 - 04/01/23

Doi : 10.1016/S1470-2045(22)00643-X

José Garcia-Pelaez, MSc ^a,^b,^f,^l, Rita Barbosa-Matos, MSc ^a,^c,^f,^l,^{^{†
Contributed equally}}, Silvana Lobo, MSc ^a,^c,^f,^l,^{^{†
Contributed equally}}, Alexandre Dias, MSc ^a,^f,^l,^{^{†
Contributed equally}}, Luzia Garrido, RN ^g, Sérgio Castedo, ProfMD PhD ^a,^b,^f,^g,^l,^bg, Sónia Sousa, BSc ^a,^f,^l, Hugo Pinheiro, MD PhD ^a,^f,^h,^l, Liliana Sousa, MSc ^a,^f,^i,^l, Rita Monteiro, MSc ^a,^f, Joaquin J Maqueda, MSc ^a,^f,^j, Susana Fernandes, PhD ^a, Fátima Carneiro, ProfMD PhD ^a,^b,^f,^g,^l,^bg, Nádia Pinto, PhD ^a,^d,^f,^l, Carolina Lemos, PhD ^a,^c,^e,^l, Carla Pinto, MSc ^k,^l, Manuel R Teixeira, MD PhD ^c,^k,^l,^bg, Stefan Aretz, ProfMD PhD ^m,^o,^bh, Svetlana Bajalica-Lagercrantz, MD PhD ^p,^q,^r,^bi, Judith Balmaña, MD PhD ^s,^bj, Ana Blatnik, MD ^u,^bk, Patrick R Benusiglio, MD ^v, Maud Blanluet, PharmD ^w, Vincent Bours, MD PhD ^x,^y,^bl, Hilde Brems, PhD ^z, Joan Brunet, MD PhD ^aa,^bj, Daniele Calistri, PhD ^ab, Gabriel Capellá, MD PhD ^ac,^ad,^bj, Sergio Carrera, MD ^ae, Chrystelle Colas, MD PhD ^w,^bm, Karin Dahan, MD PhD ^af, Robin de Putter, MD ^ag,^bn, Camille Desseignés, MSc ^v, Elena Domínguez-Garrido, PhD ^ah, Conceição Egas, PhD ^ai, D Gareth Evans, ProfMD ^aj,^ak, Damien Feret, MSc ^af, Eleanor Fewings, PhD ^al, Rebecca C Fitzgerald, ProfMD ^am, Florence Coulet, PharmD PhD ^v, María Garcia-Barcina, MD PhD ^an, Maurizio Genuardi, ProfMD ^ao,^ap,^bo, Lisa Golmard, PharmD PhD ^w, Karl Hackmann, PhD ^aq,^ar,^as,^at, Helen Hanson, MD ^av, Elke Holinski-Feder, ProfMD ^aw,^ax,^bp, Robert Hüneburg, MD ^n,^o,^bh, Mateja Krajc, MD PhD ^u,^bk, Kristina Lagerstedt-Robinson, PhD ^p,^q,^bi, Conxi Lázaro, PhD ^ac,^ad,^bj, Marjolijn J L Ligtenberg, ProfMD ^ay,^az,^ba,^bq, Cristina Martínez-Bouzas, PhD ^bb, Sonia Merino, MD ^an, Geneviève Michils, PhD ^z, Srdjan Novaković, ProfPhD ^t, Ana Patiño-García, ProfPhD ^bc, Guglielmina Nadia Ranzani, ProfBSc PhD ^bd, Evelin Schröck, ProfMD ^aq,^ar,^as,^at,^au,^br, Inês Silva, MSc ^be, Catarina Silveira, MSc ^be, José L Soto, BSc PhD ^bf, Isabel Spier, MD ^m,^o,^bh, Verena Steinke-Lange, MD ^aw,^ax,^bp, Gianluca Tedaldi, PhD ^ab, María-Isabel Tejada, PhD ^bb, Emma R Woodward, MD PhD ^aj,^ak, Marc Tischkowitz, ProfMD PhD ^al, Nicoline Hoogerbrugge, ProfMD PhD ^ay,^ba,^bq, Carla Oliveira, ProfPhD ^a,^b,^f,^l,^bg,⁎

^a Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal

^b Faculty of Medicine, University of Porto, Porto, Portugal

^c Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal

^d Center of Mathematics, University of Porto, Porto, Portugal

^e Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal

^f Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal

^g Centro Hospitalar Universitário São João, Porto, Portugal

^h Serviço de Medicina Interna, Centro Hospitalar Tâmega e Sousa, Penafiel, Portugal

ⁱ Escola de Economia e Gestão, Universidade do Minho, Braga, Portugal

^j Bioinf2Bio, Porto, Portugal

^k Department of Laboratory Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal

^l Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal

^m Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany

ⁿ Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany

^o National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany

^p Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

^q Department of Clinical Genetics, Cancer Genetic Unit, Karolinska University Hospital Solna, Stockholm, Sweden

^r Cancer Theme, Karolinska University Hospital Solna, Stockholm, Sweden

^s Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain

^t Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia

^u Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia

^v Medical Genetics Department, Pitié-Salpêtrière Hospital, AP-HP and Sorbonne University, Paris, France

^w Service de Génétique Oncologique, Institut Curie, Paris, France

^x Laboratory of Human Genetics, GIGA Institute, University of Liège, Liège, Belgium

^y Center of Genetics, University Hospital, Liège, Belgium

^z Department of Human Genetics, University of Leuven, Leuven, Belgium

^aa Hereditary Cancer Programme, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research and Girona Biomedical Research Institute, Barcelona-Girona, Spain

^ab Laboratorio di Bioscienze, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy

^ac Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain

^ad Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

^ae Oncology Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain

^af Center of Human Genetics, IPG, Gosselies, Belgium

^ag Clinical Genetics Department, University Hospital of Ghent, Ghent, Belgium

^ah Molecular Diagnostics Laboratory, Fundación Rioja Salud, Logroño, Spain

^ai CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

^aj Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK

^ak Manchester Centre for Genomic Medicine, Manchester, UK

^al Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK

^am Early Cancer Institute, University of Cambridge, Cambridge, UK

^an Genetics Unit, Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Bilbao, Bizkaia, Spain

^ao Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Salute Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy

^ap UOC Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy

^aq Institute for Clinical Genetics, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

^ar National Center for Tumor Diseases, Dresden, Germany: German Cancer Research Center, Heidelberg, Germany

^as Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany

^at German Cancer Consortium, Dresden, Germany

^au Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

^av SouthWest Thames Regional Genetics Service, St George’s University Hospitals NHS Foundation Trust, London, UK

^aw Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany

^ax Medizinisch Genetisches Zentrum, Munich, Germany

^ay Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands

^az Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands

^ba Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands

^bb Genetics Service, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Cruces-Barakaldo, Bizkaia, Spain

^bc 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

^bd Department of Biology and Biotechnology, University of Pavia, Pavia, Italy

^be GenoMed—Diagnósticos de Medicina Molecular, Lisbon, Portugal

^bf Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain

^bg European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Porto, Portugal

^bh ERN GENTURIS, Bonn, Germany

^bi ERN GENTURIS, Stockholm, Sweden

^bj ERN GENTURIS, Barcelona, Spain

^bk ERN GENTURIS, Ljubljana, Slovenia

^bl ERN GENTURIS, Liège, Belgium

^bm ERN GENTURIS, Paris, France

^bn ERN GENTURIS, Ghent, Belgium

^bo ERN GENTURIS, Rome, Italy

^bp ERN GENTURIS, Munich, Germany

^bq ERN GENTURIS, Nijmegen, Netherlands

^br ERN GENTURIS, Dresden, Germany

^* Correspondence to: Prof Carla Oliveira, Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto 4200-135, Portugal Instituto de Investigação e Inovação em Saúde (i3S) University of Porto Porto 4200-135 Portugal

Summary

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.

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Vol 24 - N° 1

P. 91-106 - janvier 2023 Retour au numéro

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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 - 04/01/23

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