CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype.

Autor:	Corso G; Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Marino E; Clinic Unit of Oncogenomics, IEO, IRCCS, Milan, Italy., Zanzottera C; Division of Cancer Prevention and Genetics, IEO, IRCCS, Milan, Italy., Oliveira C; Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.; Faculty of Medicine, University of Porto, Porto, Portugal.; Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal., Bernard L; Clinic Unit of Oncogenomics, IEO, IRCCS, Milan, Italy., Macis D; Division of Cancer Prevention and Genetics, IEO, IRCCS, Milan, Italy., Figueiredo J; Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.; Faculty of Medicine, University of Porto, Porto, Portugal.; Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal., Pereira J; Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.; Faculty of Medicine, University of Porto, Porto, Portugal.; Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal., Carneiro P; Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.; Faculty of Medicine, University of Porto, Porto, Portugal.; Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal., Massari G; Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy., Barberis M; Division of Pathology, IEO, IRCCS, Milan, Italy., De Scalzi AM; Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy., Taormina SV; Division of Pathology, IEO, IRCCS, Milan, Italy., Sajjadi E; Division of Pathology, IEO, IRCCS, Milan, Italy., Sangalli C; Data Management, IEO, IRCCS, Milan, Italy., Gandini S; Department of Experimental Oncology, IEO, IRCCS, Milan, Italy., D'Ecclesiis O; Department of Experimental Oncology, IEO, IRCCS, Milan, Italy., Trovato CM; Division of Endoscopy, IEO, IRCCS, Milan, Italy., Rotili A; Division of Breast Imaging, IEO, IRCCS, Milan, Italy., Pesapane F; Division of Breast Imaging, IEO, IRCCS, Milan, Italy., Nicosia L; Division of Breast Imaging, IEO, IRCCS, Milan, Italy., La Vecchia C; Department of Clinical Sciences and Community Health, Branch of Medical Statistics, Biometry and Epidemiology 'G.A. Maccacaro,' University of Milan, Milan, Italy., Galimberti V; Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy., Guerini-Rocco E; Division of Pathology, IEO, IRCCS, Milan, Italy., Bonanni B; Division of Cancer Prevention and Genetics, IEO, IRCCS, Milan, Italy., Veronesi P; Division of Breast Surgery, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Jazyk:	angličtina
Zdroj:	JAMA network open [JAMA Netw Open] 2024 Apr 01; Vol. 7 (4), pp. e247862. Date of Electronic Publication: 2024 Apr 01.
DOI:	10.1001/jamanetworkopen.2024.7862
Abstrakt:	Importance: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. Objectives: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. Design, Setting, and Participants: This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Main Outcomes and Measures: Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Results: Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). Conclusions and Relevance: In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.
Databáze:	MEDLINE
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