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Cancers
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Hereditary Gastric Cancer—Molecular Basis and Diagnosis
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Hereditary Gastric Cancer—Molecular Basis and Diagnosis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 19723

Special Issue Editors

Prof. Dr. Carla Oliveira

E-Mail Website
Guest Editor
Expression Regulation in Cancer Group, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Ipatimup - Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal.
Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Interests: E-cadherin; CDH1; sporadic gastric cancer; hereditary diffuse gastric cancer; HDGC; regulatory elements; gene expression; functional genomics; CD44v6; cancer biomarkers
Dr. Gabriela M. Almeida

E-Mail Website
Co-Guest Editor
Expression Regulation in Cancer Group, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Ipatimup - Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal.
Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Interests: sporadic gastric cancer; hereditary gastric cancer; therapy response; therapy resistance; cancer therapeutic targets; intra-tumor heterogeneity; cancer biomarkers

Special Issue Information

Dear Colleague,

Hereditary forms of gastric cancer occur in >3% of all cases, and two monogenic GC-associated syndromes have a confirmed genetic cause: hereditary diffuse gastric cancer (HDGC), caused by CDH1- and CTNNA1-inactivating variants; and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), caused by APC promoter 1B regulatory variants. Familial intestinal gastric cancer (FIGC) remains unsolved. Other hereditary gastric cancer candidate genes remain formally unproven.

Many confirmed HDGC, GAPPS, and FIGC cases remain genetically unexplained, raising the need for research on novel inherited predisposing factors and improved diagnosis. In this Special Issue devoted to “Hereditary Gastric Cancer—Molecular Basis and Diagnosis”, we welcome the submission of original research articles as well as critical reviews on this topic.

Prof. Dr. Carla Oliveira
Dr. Gabriela M. Almeida
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hereditary gastric cancer syndromes
  • tumor spectrum
  • diffuse gastric cancer
  • lobular breast cancer
  • genetic diagnosis of hereditary gastric cancer
  • candidate genes
  • risk factors
  • somatic mosaicism

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Published Papers (5 papers)

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Research

22 pages, 2571 KiB  
Article
E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib
by Nicola Bougen-Zhukov, Lyvianne Decourtye-Espiard, Wilson Mitchell, Kieran Redpath, Jacqui Perkinson, Tanis Godwin, Michael A. Black and Parry Guilford
Cancers 2022, 14(7), 1609; https://doi.org/10.3390/cancers14071609 - 22 Mar 2022
Cited by 5 | Viewed by 3373
Abstract
The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT [...] Read more.
The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin. Full article
(This article belongs to the Special Issue Hereditary Gastric Cancer—Molecular Basis and Diagnosis)
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19 pages, 3866 KiB  
Article
E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors
by Lyvianne Decourtye-Espiard, Nicola Bougen-Zhukov, Tanis Godwin, Tom Brew, Emily Schulpen, Michael A. Black and Parry Guilford
Cancers 2022, 14(1), 175; https://doi.org/10.3390/cancers14010175 - 30 Dec 2021
Cited by 11 | Viewed by 3050
Abstract
Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). [...] Read more.
Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1−/− breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/− murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers. Full article
(This article belongs to the Special Issue Hereditary Gastric Cancer—Molecular Basis and Diagnosis)
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27 pages, 8869 KiB  
Article
Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking
by Tom Brew, Nicola Bougen-Zhukov, Wilson Mitchell, Lyvianne Decourtye, Emily Schulpen, Yasmin Nouri, Tanis Godwin and Parry Guilford
Cancers 2022, 14(1), 102; https://doi.org/10.3390/cancers14010102 - 26 Dec 2021
Cited by 7 | Viewed by 3727
Abstract
Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken [...] Read more.
Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1−/− MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC. Full article
(This article belongs to the Special Issue Hereditary Gastric Cancer—Molecular Basis and Diagnosis)
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18 pages, 5797 KiB  
Article
The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing
by Rita Barbosa-Matos, Rafaela Leal Silva, Luzia Garrido, Ana Cerqueira Aguiar, José Garcia-Pelaez, Ana André, Susana Seixas, Sónia Passos Sousa, Luísa Ferro, Lúcia Vilarinho, Irene Gullo, Vitor Devezas, Renata Oliveira, Susana Fernandes, Susy Cabral Costa, André Magalhães, Manuela Baptista, Fátima Carneiro, Hugo Pinheiro, Sérgio Castedo and Carla Oliveiraadd Show full author list remove Hide full author list
Cancers 2021, 13(17), 4464; https://doi.org/10.3390/cancers13174464 - 4 Sep 2021
Cited by 7 | Viewed by 3325
Abstract
Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this [...] Read more.
Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum. Full article
(This article belongs to the Special Issue Hereditary Gastric Cancer—Molecular Basis and Diagnosis)
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Graphical abstract

18 pages, 758 KiB  
Article
CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation
by Matthew G. K. Benesch, Stuart R. Bursey, Andrew C. O’Connell, Morag G. Ryan, Carrie L. Howard, Cecily C. Stockley and Alexander Mathieson
Cancers 2021, 13(11), 2622; https://doi.org/10.3390/cancers13112622 - 26 May 2021
Cited by 20 | Viewed by 5305
Abstract
Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The [...] Read more.
Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking. Full article
(This article belongs to the Special Issue Hereditary Gastric Cancer—Molecular Basis and Diagnosis)
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