Title |
Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer
|
---|---|
Published in |
Gastric Cancer, May 2023
|
DOI | 10.1007/s10120-023-01395-0 |
Pubmed ID | |
Authors |
Celina São José, José Garcia-Pelaez, Marta Ferreira, Oscar Arrieta, Ana André, Nelson Martins, Samantha Solís, Braulio Martínez-Benítez, María Luisa Ordóñez-Sánchez, Maribel Rodríguez-Torres, Anna K. Sommer, Iris B. A. W. te Paske, Carlos Caldas, Marc Tischkowitz, Maria Teresa Tusié, Nicoline Hoogerbrugge, German Demidov, Richarda M. de Voer, Steve Laurie, Carla Oliveira |
Abstract |
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. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 15% |
Spain | 2 | 15% |
United Kingdom | 1 | 8% |
New Zealand | 1 | 8% |
Mexico | 1 | 8% |
Germany | 1 | 8% |
Portugal | 1 | 8% |
Netherlands | 1 | 8% |
Unknown | 3 | 23% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 6 | 46% |
Scientists | 4 | 31% |
Practitioners (doctors, other healthcare professionals) | 3 | 23% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 14 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 5 | 36% |
Student > Ph. D. Student | 1 | 7% |
Professor | 1 | 7% |
Unknown | 7 | 50% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 5 | 36% |
Medicine and Dentistry | 1 | 7% |
Unknown | 8 | 57% |