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
| Autor: | José Garcia-Pelaez, Rita Barbosa-Matos, Silvana Lobo, Alexandre Dias, Luzia Garrido, Sérgio Castedo, Sónia Sousa, Hugo Pinheiro, Liliana Sousa, Rita Monteiro, Joaquin J Maqueda, Susana Fernandes, Fátima Carneiro, Nádia Pinto, Carolina Lemos, Carla Pinto, Manuel R Teixeira, Stefan Aretz, Svetlana Bajalica-Lagercrantz, Judith Balmaña, Ana Blatnik, Patrick R Benusiglio, Maud Blanluet, Vincent Bours, Hilde Brems, Joan Brunet, Daniele Calistri, Gabriel Capellá, Sergio Carrera, Chrystelle Colas, Karin Dahan, Robin de Putter, Camille Desseignés, Elena Domínguez-Garrido, Conceição Egas, D Gareth Evans, Damien Feret, Eleanor Fewings, Rebecca C Fitzgerald, Florence Coulet, María Garcia-Barcina, Maurizio Genuardi, Lisa Golmard, Karl Hackmann, Helen Hanson, Elke Holinski-Feder, Robert Hüneburg, Mateja Krajc, Kristina Lagerstedt-Robinson, Conxi Lázaro, Marjolijn J L Ligtenberg, Cristina Martínez-Bouzas, Sonia Merino, Geneviève Michils, Srdjan Novaković, Ana Patiño-García, Guglielmina Nadia Ranzani, Evelin Schröck, Inês Silva, Catarina Silveira, José L Soto, Isabel Spier, Verena Steinke-Lange, Gianluca Tedaldi, María-Isabel Tejada, Emma R Woodward, Marc Tischkowitz, Nicoline Hoogerbrugge, Carla Oliveira |
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| Přispěvatelé: | Institut Català de la Salut, [Garcia-Pelaez J] 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 R, Lobo S] 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 A] 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 L] Centro Hospitalar Universitário São João, Porto, Portugal. [Castedo S] 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. [Balmaña J] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. ERN GENTURIS, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias gástricas [ENFERMEDADES]
Genotype Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] enfermedades de la piel y tejido conjuntivo::enfermedades de la piel::enfermedades de la mama [ENFERMEDADES] Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES] Mutation Missense Breast Neoplasms All institutes and research themes of the Radboud University Medical Center Germ Cells/pathology Antigens CD Stomach Neoplasms Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Humans Genetic Predisposition to Disease Genotip Càncer Germ-Line Mutation fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS] Cancer Retrospective Studies Breast Neoplasms/epidemiology Cadherins/genetics Antigens CD/genetics Stomach Neoplasms/epidemiology Cadherins Pedigree Fenotip Carcinoma Lobular Germ Cells Phenotype Oncology Aparell digestiu - Càncer - Aspectes genètics Mama - Càncer - Aspectes genètics Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Stomach Neoplasms [DISEASES] Female |
| Zdroj: | Garcia-Pelaez, J, Barbosa-Matos, R, Lobo, S, Dias, A, Garrido, L, Castedo, S, Sousa, S, Pinheiro, H, Sousa, L, Monteiro, R, Maqueda, J J, Fernandes, S, Carneiro, F, Pinto, N, Lemos, C, Pinto, C, Teixeira, M R, Aretz, S, Bajalica-Lagercrantz, S, Balmaña, J, Blatnik, A, Benusiglio, P R, Blanluet, M, Bours, V, Brems, H, Brunet, J, Calistri, D, Capellá, G, Carrera, S, Colas, C, Dahan, K, de Putter, R, Desseignés, C, Domínguez-Garrido, E, Egas, C, Evans, D G, Feret, D, Fewings, E, Fitzgerald, R C, Coulet, F, Garcia-Barcina, M, Genuardi, M, Golmard, L, Hackmann, K, Hanson, H, Holinski-Feder, E, Hüneburg, R, Krajc, M, Lagerstedt-Robinson, K, Lázaro, C, Ligtenberg, M J L, Martínez-Bouzas, C, Merino, S, Michils, G, Novaković, S, Patiño-García, A, Ranzani, G N, Schröck, E, Silva, I, Silveira, C, Soto, J L, Spier, I, Steinke-Lange, V, Tedaldi, G, Tejada, M-I, Woodward, E R, Tischkowitz, M, Hoogerbrugge, N & Oliveira, C 2023, ' 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 ', The Lancet. Oncology, vol. 24, no. 1, pp. 91-106 . https://doi.org/10.1016/S1470-2045(22)00643-X Lancet Oncology, 24, 1, pp. 91-106 Scientia Lancet Oncology, 24, 91-106 |
| ISSN: | 1470-2045 |
| DOI: | 10.1016/S1470-2045(22)00643-X |
| Popis: | Genotype; Cancer phenotypes; Genetic tumour Genotip; Fenotips del càncer; Tumor genètic Genotipo; Fenotipos del cáncer; Tumor genético 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. 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. |
| Databáze: | OpenAIRE |
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