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This study characterizes an inherited mechanism underlying extremely early-onset gastric cancer and atypical, high-penetrance HDGC. Methods Whole-exome re-analysis plus ATAC-seq/4C-seq identified chromatin regions and CDH1 promoter interactors; functional effects were tested via CRISPR-Cas9 and RNA-seq with pathway analysis. Results A germline 23 kb CDH1-TANGO6 deletion associated with multiple early cancers disrupted accessible chromatin and regulatory interactions. Edited cells showed strongest CDH1 mRNA downregulation and altered adhesion, type-I interferon immune and oncogenic signalling pathways. Conclusion Regulatory elements downstream of CDH1 form a chromatin network controlling CDH1 expression and transcriptome, explaining high penetrance and very young onset.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/combined-loss-of-cdh1-and-downstream-regulatory-sequences-drive-early-onset-diffuse-gastric-cancer-and-increase-penetrance-of-hereditary-diffuse-gastric-cancer/384927/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/combined-loss-of-cdh1-and-downstream-regulatory-sequences-drive-early-onset-diffuse-gastric-cancer-and-increase-penetrance-of-hereditary-diffuse-gastric-cancer/384927.png","ImageObject",300,407,{"name":42,"@type":43},"Alex 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analysis.",{"name":70,"@type":61,"acceptedAnswer":71},"What cellular effects were observed when the CDH1-TANGO6 deletion was modeled?",{"text":72,"@type":64},"CRISPR-edited cells mimicking the deletion showed the strongest CDH1 mRNA downregulation and greater impact on adhesion-associated, type-I interferon immune-associated, and oncogenic signalling pathways compared with wild-type or CDH1-deleted cells.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},384927,1790512034,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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\nCombined loss of CDH1 and downstream regulatory sequences drive early‑onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer  \nCelina São José,, · José Garcia‑Pelaez,, · Marta Ferreira,, · Oscar Arrieta · Ana André, · Nelson Martins,,, et al. [full author details at the end of the article]  \nReceived: 8 March 2023 / Accepted: 30 April 2023 / Published online: 30 May 2023 © The Author(s) 2023  \nAbstract  \nBackground 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.  \nMethods 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.  \nResults 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 ina cancer prevention pathway of care.  \nConclusion 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.  \nCelina São José and José Garcia-Pelaez contributed equally to this work.  \nThe collaborators names associated with Solve-RD DITFGENTURIS are given in acknowledgements sections.  \nGraphical abstract  \nKeywords CDH1 · Hereditary diffuse gastric cancer · Regulatory elements · Copy number variants · Deletion · Type-I interferon immune response  \nIntroduction  \nPathogenic and likely pathogenic germline truncating singlenucleotide (SNVs) and copy number variants (CNVs) affecting the CDH1 coding sequence [1–3], as well as, truncating CTNNA1 SNVs [4, 5] cause hereditary diffuse gastric cancer (HDGC) syndrome [3, 5, 6] . CDH1 and CTNNA1 genes encode epithelial adherens junctions proteins, E-cadherinand αE-catenin respectively [7, 8], whose loss of function reduces cell–cell adhesion and increases invasiveness and cell survival, amongst other consequences [7, 9] . HDGC is autosomal-dominant and predisposes to diffuse gastric cancer (DGC) and lobular breast cancer (LBC) [1, 3] .  \nIn CDH1-associated HDGC, the cumulative DGC incidence ranges from 42 to 72% in males [10, 11], and from 33 to 55% in females, whilst the risk of LBC ranges from 39 to 55% in females, by 80 years of age [10–13] . Even taking into account that estimates are likely to be biassed, either due to patient geographical origin or due to clinical ascertainment [11], the risk of developing DGC or LBC remains high across different cohorts and studies [3] . Individuals with suspected HDGC are identified and refer","cbCaimqAaXh8inyh","https://ap.wps.com/l/cbCaimqAaXh8inyh","pdf",5170119,14,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusion\n# Introduction","[{\"question\":\"What genetic finding is linked to extremely early-onset diffuse gastric cancer in the study?\",\"answer\":\"The study identifies a germline heterozygous 23 kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six occurring before age 30.\"},{\"question\":\"How did the researchers determine the mechanism behind the high penetrance?\",\"answer\":\"They evaluated accessible chromatin and CDH1 promoter interactors in normal stomach using ATAC-seq and 4C-seq, then used CRISPR-Cas9 to mimic the deletion and assessed effects with RNA-seq and pathway analysis.\"},{\"question\":\"What cellular effects were observed when the CDH1-TANGO6 deletion was modeled?\",\"answer\":\"CRISPR-edited cells mimicking the deletion showed the strongest CDH1 mRNA downregulation and greater impact on adhesion-associated, type-I interferon immune-associated, and oncogenic signalling pathways compared with wild-type or CDH1-deleted cells.\"}]","Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer | PDF",1790265895,35]