Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes– a collaborative multicentre endeavour within the project Solve-RD

Sommer, Anna; Paske, Iris B A W Te; Garcia-Pelaez, José; Laner, Andreas; Holinski‐Feder, Elke; Steinke‐Lange, Verena; Peters, Sophia; Valle, Laura; Spier, Isabel; Huntsman, David G.

doi:10.1016/j.ejmg.2022.104475

Cited by 2 publications

(2 citation statements)

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“…WES from HDGC-suspected family [ 19 ] was re-analyzed and screened for CNVs using three variant callers (ExomeDepth [ 30 ], ClinCNV [ 31 ] and Manta [ 32 ]) in tumour risk syndromes-associated genes (supplementary table 1) and annotated using AnnotSV [ 33 ]. Candidate calls were prioritized considering quality scores, calling by more than one caller and visual evaluation using Integrated Genome Viewer (IGV).…”

Section: Materials/subjects and Methodsmentioning

confidence: 99%

“…Many families fulfilling the 2020 HDGC clinical criteria remain genetically unexplained, despite the use of candidate-gene, whole-exome (WES), and whole-genome (WGS) sequencing approaches [ 6 , 19 ]. Missing hereditability in such families may derive from screening approaches excluding CNV analysis or by technical limitations still existing in next-generation sequencing (NGS) protocols and analyses pipelines [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer

et al. 2023

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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

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