{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sao Jose C"],"funding":["Fundação para a Ciência e a Tecnologia","Universidade do Porto","NIHR Cambridge Biomedical Research Centre","Horizon 2020"],"pagination":["653-666"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10361908"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(5)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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."],"journal":["Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association"],"pubmed_title":["Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer."],"pmcid":["PMC10361908"],"funding_grant_id":["H2020-SC1-2017-Single-Stage-RTD","2020.05763.BD","PTDC/BTM-TEC/6706/2020","SFRH/BD/140796/2018","BRC-1215-20014"],"pubmed_authors":["Ligtenberg M","Spruijt L","Paske IT","Tischkowitz M","Capella G","Peters S","Holinski-Feder E","Meinhardt A","Kets CM","Steinke-Lange V","Sao Jose C","Spier I","Laner A","Mensenkamp A","Schrock E","van Zelst-Stams W","van der Post R","Fernandes S","Solve-RD DITF-GENTURIS","Valle L","Arrieta O","Ferreira M","Evans G","Rodriguez-Torres M","Andre A","de Voer RM","Garcia-Pelaez J","Te Paske IBAW","Caldas C","Aretz S","Sommer A","Hoogerbrugge N","Jahn A","Huntsman D","Garrido L","Ordonez-Sanchez ML","Laurie S","Tusie MT","Martinez-Benitez B","Demidov G","Oliveira C","William D","Quintana I","van Herwaarden Y","Sommer AK","Castedo S","Martins N","Solis S"],"additional_accession":[]},"is_claimable":false,"name":"Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.","description":"<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Sep","modification":"2026-05-29T21:11:42.917Z","creation":"2025-04-05T12:36:07.01Z"},"accession":"S-EPMC10361908","cross_references":{"pubmed":["37249750"],"doi":["10.1007/s10120-023-01395-0"]}}