Portal de investigação
Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer
Data de publicação:
Data Ahead of Print:
Autores da FMUP
Participantes de fora da FMUP
- Sao José, C
- Garcia-Pelaez, J
- Ferreira, M
- Arrieta, O
- André, A
- Martins, N
- Solís, S
- Martínez-Benítez, B
- Ordóñez-Sánchez, ML
- Rodríguez-Torres, M
- Sommer, AK
- te Paske, IBAW
- Caldas, C
- Tischkowitz, M
- Tusié, MT
- Hoogerbrugge, N
- Demidov, G
- de Voer, RM
- Laurie, S
- Solve-RD DITF-GENTURIS
Abstract
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. [GRAPHICS] .
Dados da publicação
- ISSN/ISSNe:
- 1436-3291, 1436-3305
- Tipo:
- Article
- Páginas:
- 653-666
- Link para outro recurso:
- www.scopus.com
Gastric Cancer Springer Japan
Citações Recebidas na Scopus: 5
Documentos
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Filiações
Keywords
- CDH1; Hereditary diffuse gastric cancer; Regulatory elements; Copy number variants; Deletion; Type-I interferon immune response
Financiamento
Proyectos asociados
E-cadherin and CD44v6 in Gastric Cancer: Role, crosstalk and clinical implications
Investigador Principal: Carla Isabel Gonçalves de Oliveira
Estudo Clínico Académico . 2021
Citar a publicação
Sao C,Garcia J,Ferreira M,Arrieta O,André A,Martins N,Solís S,Martínez B,Ordóñez ML,Rodríguez M,Sommer AK,te I,Caldas C,Tischkowitz M,Tusié MT,Hoogerbrugge N,Demidov G,de Voer RM,Laurie S,Oliveira C,Solve D. Combined loss of <i>CDH1</i> and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer. Gastric Cancer. 2023. 26. (5):p. 653-666. IF:7,400. (1).
