Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer
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Published:2023-05-30
Issue:5
Volume:26
Page:653-666
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ISSN:1436-3291
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Container-title:Gastric Cancer
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language:en
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Short-container-title:Gastric Cancer
Author:
São José Celina, Garcia-Pelaez José, Ferreira Marta, Arrieta Oscar, André Ana, Martins Nelson, Solís Samantha, Martínez-Benítez Braulio, Ordóñez-Sánchez María Luisa, Rodríguez-Torres Maribel, Sommer Anna K., te Paske Iris B. A. W., Caldas Carlos, Tischkowitz Marc, Tusié Maria Teresa, Aretz Stefan, Capella Gabriel, Castedo Sérgio, de Voer Richarda M., Evans Gareth, Fernandes Susana, Garcia-Pelaez José, Garrido Luzia, Holinski-Feder Elke, Hoogerbrugge Nicoline, Huntsman David, Jahn Arne, Kets C. Marleen, Laner Andreas, Ligtenberg Marjolijn, Meinhardt Andrea, Mensenkamp Arjen, Oliveira CarlaORCID, Peters Sophia, Quintana Isabel, Schröck Evelin, Sommer Anna, Spier Isabel, Spruijt Liesbeth, Steinke-Lange Verena, Paske Iris te, Tischkowitz Marc, Valle Laura, van der Post Rachel, van Herwaarden Yasmijn, van Zelst-Stams Wendy, William Doreen, Hoogerbrugge Nicoline, Demidov German, de Voer Richarda M., Laurie Steve, Oliveira CarlaORCID,
Abstract
Abstract
Background
Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs’ and breasts’ surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance.
Methods
Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis.
Results
We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care.
Conclusion
In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific–technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.
Graphical abstract
Funder
Horizon 2020 Fundação para a Ciência e a Tecnologia NIHR Cambridge Biomedical Research Centre Universidade do Porto
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Gastroenterology,Oncology,General Medicine
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