biostudies-literatureSao Jose CFundação para a Ciência e a TecnologiaUniversidade do PortoNIHR Cambridge Biomedical Research CentreHorizon 2020653-666https://www.ebi.ac.uk/biostudies/studies/S-EPMC10361908biostudies-literatureUnknown26(5)<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.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer AssociationCombined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.PMC10361908H2020-SC1-2017-Single-Stage-RTD2020.05763.BDPTDC/BTM-TEC/6706/2020SFRH/BD/140796/2018BRC-1215-20014Ligtenberg MSpruijt LPaske ITTischkowitz MCapella GPeters SHolinski-Feder EMeinhardt AKets CMSteinke-Lange VSao Jose CSpier ILaner AMensenkamp ASchrock Evan Zelst-Stams Wvan der Post RFernandes SSolve-RD DITF-GENTURISValle LArrieta OFerreira MEvans GRodriguez-Torres MAndre Ade Voer RMGarcia-Pelaez JTe Paske IBAWCaldas CAretz SSommer AHoogerbrugge NJahn AHuntsman DGarrido LOrdonez-Sanchez MLLaurie STusie MTMartinez-Benitez BDemidov GOliveira CWilliam DQuintana Ivan Herwaarden YSommer AKCastedo SMartins NSolis SfalseCombined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.<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.2023-01-01T00:00:00Z2023 Sep2026-05-29T21:11:42.917Z2025-04-05T12:36:07.01ZS-EPMC103619083724975010.1007/s10120-023-01395-0