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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • José Garcia-Pelaez - , Universidade do Porto (Autor:in)
  • Rita Barbosa-Matos - , Universidade do Porto (Autor:in)
  • Silvana Lobo - , Universidade do Porto (Autor:in)
  • Alexandre Dias - , Universidade do Porto (Autor:in)
  • Luzia Garrido - , São João Hospital (Autor:in)
  • Sérgio Castedo - , Universidade do Porto (Autor:in)
  • Sónia Sousa - , Universidade do Porto (Autor:in)
  • Hugo Pinheiro - , Universidade do Porto (Autor:in)
  • Liliana Sousa - , Universidade do Porto (Autor:in)
  • Rita Monteiro - , Universidade do Porto (Autor:in)
  • Joaquin J Maqueda - , Universidade do Porto (Autor:in)
  • Susana Fernandes - , Universidade do Porto (Autor:in)
  • Fátima Carneiro - , Universidade do Porto (Autor:in)
  • Nádia Pinto - , Universidade do Porto (Autor:in)
  • Carolina Lemos - , Universidade do Porto (Autor:in)
  • Carla Pinto - , Instituto Português de Oncologia (IPO) do Porto (Autor:in)
  • Manuel R Teixeira - , Universidade do Porto (Autor:in)
  • Stefan Aretz - , Universitätsklinikum Bonn (Autor:in)
  • Svetlana Bajalica-Lagercrantz - , Karolinska-Universitätskrankenhaus (Autor:in)
  • Judith Balmaña - , Hospital Universitari Vall d'Hebron (Autor:in)
  • Ana Blatnik - , Institute of Oncology Ljubljana (Autor:in)
  • Patrick R Benusiglio - , Sorbonne Université (Autor:in)
  • Maud Blanluet - , Institut Curie (Autor:in)
  • Vincent Bours - , University of Liege (Autor:in)
  • Hilde Brems - , Universitair Ziekenhuis (UZ) Leuven (Autor:in)
  • Joan Brunet - , Institut d'Investigació Biomedica de Bellvitge (IDIBELL) (Autor:in)
  • Daniele Calistri - , Laboratorio di Bioscienze (Autor:in)
  • Gabriel Capellá - , Institut d'Investigació Biomedica de Bellvitge (IDIBELL) (Autor:in)
  • Sergio Carrera - , Hospital de Cruces (Autor:in)
  • Chrystelle Colas - , Institut Curie (Autor:in)
  • Karin Dahan - , Technische Universität Dresden (Autor:in)
  • Robin de Putter - , Ghent University Hospital (Autor:in)
  • Camille Desseignés - , Sorbonne Université (Autor:in)
  • Elena Domínguez-Garrido - , Molecular Diagnostics Laboratory (Autor:in)
  • Conceição Egas - , University of Coimbra (Autor:in)
  • D Gareth Evans - , University of Manchester (Autor:in)
  • Damien Feret - , Technische Universität Dresden (Autor:in)
  • Eleanor Fewings - , University of Cambridge (Autor:in)
  • Rebecca C Fitzgerald - , University of Cambridge (Autor:in)
  • Florence Coulet - , Sorbonne Université (Autor:in)
  • María Garcia-Barcina - , Hospital de Basurto (Autor:in)
  • Maurizio Genuardi - , Sezione di Medicina Genomica (Autor:in)
  • Lisa Golmard - , Institut Curie (Autor:in)
  • Karl Hackmann - , Institut für Klinische Genetik (Autor:in)
  • Helen Hanson - , St George's University Hospitals NHS Foundation Trust (Autor:in)
  • Elke Holinski-Feder - , Medizinische Klinik und Poliklinik I (Autor:in)
  • Robert Hüneburg - , Universitätsklinikum Bonn (Autor:in)
  • Mateja Krajc - , Institute of Oncology Ljubljana (Autor:in)
  • Kristina Lagerstedt-Robinson - , Karolinska-Universitätskrankenhaus (Autor:in)
  • Conxi Lázaro - , Institut d'Investigació Biomedica de Bellvitge (IDIBELL) (Autor:in)
  • Marjolijn J L Ligtenberg - , Radboud University Medical Center (Autor:in)
  • Cristina Martínez-Bouzas - , Hospital de Cruces (Autor:in)
  • Sonia Merino - , Hospital de Basurto (Autor:in)
  • Geneviève Michils - , Universitair Ziekenhuis (UZ) Leuven (Autor:in)
  • Srdjan Novaković - , Institute of Oncology Ljubljana (Autor:in)
  • Ana Patiño-García - , Unidad de Medicina Genómica y Pediatría (Autor:in)
  • Guglielmina Nadia Ranzani - , Università degli Studi di Pavia (Autor:in)
  • Evelin Schröck - , Institut für Klinische Genetik (Autor:in)
  • Inês Silva - , GenoMed-Diagnósticos de Medicina Molecular (Autor:in)
  • Catarina Silveira - , GenoMed-Diagnósticos de Medicina Molecular (Autor:in)
  • José L Soto - , Hospital General Universitario de Elche (Autor:in)
  • Isabel Spier - , Universitätsklinikum Bonn (Autor:in)
  • Verena Steinke-Lange - , Medizinische Klinik und Poliklinik I (Autor:in)
  • Gianluca Tedaldi - , Laboratorio di Bioscienze (Autor:in)
  • María-Isabel Tejada - , Hospital de Cruces (Autor:in)
  • Emma R Woodward - , University of Manchester (Autor:in)
  • Marc Tischkowitz - , University of Cambridge (Autor:in)
  • Nicoline Hoogerbrugge - , Radboud University Medical Center (Autor:in)
  • Carla Oliveira - , Universidade do Porto (Autor:in)

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).

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)91-106
Seitenumfang16
FachzeitschriftThe Lancet Oncology
Jahrgang24
Ausgabenummer1
PublikationsstatusVeröffentlicht - Jan. 2023
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC9810541
Scopus 85145669093
WOS 000928248100001

Schlagworte

Ziele für nachhaltige Entwicklung

ASJC Scopus Sachgebiete

Schlagwörter

  • Female, Humans, Antigens, CD/genetics, Breast Neoplasms/epidemiology, Cadherins/genetics, Carcinoma, Lobular, Genetic Predisposition to Disease, Genotype, Germ Cells/pathology, Germ-Line Mutation, Pedigree, Phenotype, Retrospective Studies, Stomach Neoplasms/epidemiology, Mutation, Missense, Mutations, Families, E-cadherin, Guidelines, Gastric-cancer

Bibliotheksschlagworte