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1
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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2
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São José C, Pereira C, Ferreira M, André A, Osório H, Gullo I, Carneiro F, Oliveira C. 3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer. BIOLOGY 2023; 12:803. [PMID: 37372088 DOI: 10.3390/biology12060803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/25/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
Cadherins are cell-cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. CDH1 and CDH3 mRNA expression was obtained from 42 gastric tumours' RNA-seq data. CRISPR-Cas9 was used to knock out CDH1 and a putative regulatory element. CDH1-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a CDH1 promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess CDH1/E-cadherin and CDH3/P-cadherin expression. In 42% of gastric tumours analysed, CDH1 to CDH3 switch was observed. CDH1 knockout triggered CDH1/E-cadherin complete loss and CDH3/P-cadherin expression increase at plasma membrane. This switch, likely rescuing adherens junctions, increased cell migration/proliferation, commonly observed in aggressive tumours. E- to P-cadherin switch accompanied increased CDH1 promoter interactions with CDH3-eQTL, absent in normal stomach and parental cells. CDH3-eQTL deletion promotes CDH3/CDH1 reduced expression. These data provide evidence that loss of CDH1/E-cadherin expression alters the CDH3 locus chromatin conformation, allowing a CDH1 promoter interaction with a CDH3-eQTL, and promoting CDH3/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.
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Affiliation(s)
- Celina São José
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Carla Pereira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Marta Ferreira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Doctoral Program in Computer Sciences, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Ana André
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
| | - Hugo Osório
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Irene Gullo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Fátima Carneiro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Carla Oliveira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
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3
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Lim HJ, Zhuang L, Fitzgerald RC. Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications. J Exp Clin Cancer Res 2023; 42:57. [PMID: 36869400 PMCID: PMC9985294 DOI: 10.1186/s13046-023-02622-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.
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Affiliation(s)
- Hui Jun Lim
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK.
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | - Lizhe Zhuang
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
| | - Rebecca C Fitzgerald
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
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Amalia R, Panenggak NSR, Doohan D, Rezkitha YAA, Waskito LA, Syam AF, Lubis M, Yamaoka Y, Miftahussurur M. A comprehensive evaluation of an animal model for Helicobacter pylori-associated stomach cancer: Fact and controversy. Helicobacter 2023; 28:e12943. [PMID: 36627714 DOI: 10.1111/hel.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/12/2023]
Abstract
Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full-text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori.
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Affiliation(s)
- Rizki Amalia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Dalla Doohan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Langgeng Agung Waskito
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan.,Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Texas, Houston, USA
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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Hereditary Diffuse Gastric Cancer: A 2022 Update. J Pers Med 2022; 12:jpm12122032. [PMID: 36556253 PMCID: PMC9783673 DOI: 10.3390/jpm12122032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and β-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.
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6
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A-Kinase Anchoring Protein 9 Promotes Gastric Cancer Progression as a Downstream Effector of Cadherin 1. JOURNAL OF ONCOLOGY 2022; 2022:2830634. [PMID: 36317124 PMCID: PMC9617730 DOI: 10.1155/2022/2830634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 10/07/2022] [Indexed: 11/24/2022]
Abstract
Background Genetic studies identified a dozen of frequently mutated genes in gastric cancer, such as cadherin 1 (CDH1) and A-kinase anchoring protein 9 (AKAP9). Of note, genetic alterations including depletion and amplification frameshift mutations of AKAP9 have been observed in 10–15% of gastric cancer patients. However, it is unknown of the expression and role of AKAP9 in gastric cancer. This study is aimed to characterize the expression and function of AKAP9 in gastric cancer. Methods Using qRT-PCR, we analyzed the mRNA levels of AKAP9 in gastric cancer patient samples. We investigated the role of AKAP9 in gastric cancer by performing cell proliferation assay, transwell assay, and mouse xenograft assay. Results AKAP9 was upregulated in gastric cancer patients. Overexpression of AKAP9 promoted cell proliferation, migration, and gastric tumor growth. Loss of CDH1 elevated AKAP9 mRNA and protein levels. Conclusion Our study demonstrates that AKAP9 functions as an oncoprotein to promote gastric cancer cell proliferation, migration, and tumor growth. Moreover, we reveal a possible molecular link showing that AKAP9 is a critical effector downstream of CDH1 in gastric cancer.
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7
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Vizgan N, Jokar TO, Enayati L, Salyana M, Gotlieb VK. Presentation and treatment of aggressive, Triple-Negative carcinosarcoma of the breast. Clin Case Rep 2022; 10:e6020. [PMID: 35865780 PMCID: PMC9291258 DOI: 10.1002/ccr3.6020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/10/2022] [Indexed: 11/10/2022] Open
Abstract
An extremely rare form of breast cancer, breast carcinosarcoma accounts for less than a percent of all breast malignancies and is highly aggressive. Composed of both cancerous epithelial and mesenchymal cell types, breast carcinosarcoma is associated with a poor prognosis compared to more common breast cancers, and typically lack the receptors typical of other breast carcinomas, which minimize potential targets for treatment. In this case report, we discuss a 56-year-old patient affected by carcinosarcoma of the breast at a T2N1 stage, and the decision-making process that factored into her treatment plan.
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Affiliation(s)
- Niels Vizgan
- Department of ChemistryWesleyan UniversityMiddletownConnecticutUSA
| | | | - Ladan Enayati
- Department of Haematology/OncologyBrookdale University Hospital and Medical CenterBrooklynNew YorkUSA
| | - Muhammad Salyana
- Department of Haematology/OncologyBrookdale University Hospital and Medical CenterBrooklynNew YorkUSA
| | - Vladimir K. Gotlieb
- Department of Haematology/OncologyBrookdale University Hospital and Medical CenterBrooklynNew YorkUSA
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8
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Carneiro F. Familial and hereditary gastric cancer, an overview. Best Pract Res Clin Gastroenterol 2022; 58-59:101800. [PMID: 35988963 DOI: 10.1016/j.bpg.2022.101800] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 04/11/2022] [Accepted: 04/24/2022] [Indexed: 02/08/2023]
Abstract
There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.
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Affiliation(s)
- Fátima Carneiro
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4100-319, Porto, Portugal; Centro Hospitalar Universitário São João, Alameda Prof. Hernani Monteiro, 4100-319, Porto, Portugal.
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9
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Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188719. [PMID: 35307354 DOI: 10.1016/j.bbcan.2022.188719] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse- and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
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Ben Aissa-Haj J, Kabbage M, Othmen H, Saulnier P, Kettiti HT, Jaballah-Gabteni A, Ferah A, Medhioub M, Khsiba A, Mahmoudi M, Maaloul A, Ben Nasr S, Chelbi E, Abdelhak S, Boubaker MS, Azzouz MM, Rouleau E. CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma. Genes (Basel) 2022; 13:genes13030400. [PMID: 35327954 PMCID: PMC8950196 DOI: 10.3390/genes13030400] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022] Open
Abstract
Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.
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Affiliation(s)
- Jihenne Ben Aissa-Haj
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
- Correspondence:
| | - Maria Kabbage
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Houcemeddine Othmen
- Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2000, South Africa;
| | - Patrick Saulnier
- Genomic Platform Molecular Biopathology Unit, URA3655 Inserm, US23 CNRS, Gustave Roussy, 94805 Villejuif, France;
| | - Haifa Tounsi Kettiti
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Amira Jaballah-Gabteni
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Azer Ferah
- Laboratory of Venoms and Therapeutic Biomolecules, LR16IPT08 Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Mouna Medhioub
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Amal Khsiba
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Moufida Mahmoudi
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Afifa Maaloul
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
| | - Sonia Ben Nasr
- Oncology Department, Military Hospital of Tunis, Tunis 1008, Tunisia;
| | - Emna Chelbi
- Department of Pathology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia;
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - M. Samir Boubaker
- Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia; (M.K.); (H.T.K.); (A.J.-G.); (A.M.); (M.S.B.)
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia;
| | - Mohamed Mousaddak Azzouz
- Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia; (M.M.); (A.K.); (M.M.); (M.M.A.)
- Faculty of Medicine Tunis, University of Tunis El Manar, Tunis 1068, Tunisia
| | - Etienne Rouleau
- Department of Biology and Pathology-Cancer Genetics Laboratory-Gustave Roussy, 94805 Villejuif, France;
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Garcia-Pelaez J, Barbosa-Matos R, São José C, Sousa S, Gullo I, Hoogerbrugge N, Carneiro F, Oliveira C. Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes. Eur J Med Genet 2021; 65:104401. [PMID: 34871783 DOI: 10.1016/j.ejmg.2021.104401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/10/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.
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Affiliation(s)
- José Garcia-Pelaez
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rita Barbosa-Matos
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Celina São José
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Sónia Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Irene Gullo
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal.
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12
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Yao C, Li Y, Luo L, Xiong Q, Zhong X, Xie F, Feng P. Identification of miRNAs and genes for predicting Barrett's esophagus progressing to esophageal adenocarcinoma using miRNA-mRNA integrated analysis. PLoS One 2021; 16:e0260353. [PMID: 34818353 PMCID: PMC8612537 DOI: 10.1371/journal.pone.0260353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
Barrett's esophagus (BE) is defined as any metaplastic columnar epithelium in the distal esophagus, which predisposes to esophageal adenocarcinoma (EAC). Yet, the mechanism through which BE develops to EAC still remain unclear. Moreover, the miRNA-mRNA regulatory network in distinguishing BE from EAC still remains poorly understood. To identify differentially expressed miRNAs (DEMs) and genes (DEGs) between EAC and BE from tissue samples, gene expression microarray datasets GSE13898, GSE26886, GSE1420 and miRNA microarray datasets GSE16456, GSE20099 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to screen the DEMs and DEGs. Pathway and functional enrichment analysis were performed by DAVID database. The protein-protein interaction (PPI) network was constructed by STRING and been visualized by Cytoscape software. Finnal, survival analysis was performed basing TCGA database. A total of 21 DEMs were identified. The enriched functions and pathways analysis inclued Epstein-Barr virus infection, herpesvirus infection and TRP channels. GART, TNFSF11, GTSE1, NEK2, ICAM1, PSMD12, CTNNB1, CDH1, PSEN1, IL1B, CTNND1, JAG1, CDH17, ITCH, CALM1 and ITGA6 were considered as the hub-genes. Hsa-miR-143 and hsa-miR-133b were the highest connectivity target gene. JAG1 was predicted as the largest number of target miRNAs. The expression of hsa-miR-181d, hsa-miR-185, hsa-miR-15b, hsa-miR-214 and hsa-miR-496 was significantly different between normal tissue and EAC. CDH1, GART, GTSE1, NEK2 and hsa-miR-496, hsa-miR-214, hsa-miR-15b were found to be correlated with survival.
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Affiliation(s)
- Chengjiao Yao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Geriatrics of the Affiliated Hospital, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yilin Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lihong Luo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qin Xiong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaowu Zhong
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- * E-mail: (PF); (XZ)
| | - Fengjiao Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Peimin Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- * E-mail: (PF); (XZ)
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13
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Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:ijms22189950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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14
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Abstract
Approximately 10% of patients with gastric cancer show familial aggregation and up to 3% are related to an inherited cancer syndrome. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of gastric cancer. Appropriate assessment of familial and genetic risk may allow a personalized approach to gastric cancer prevention through screening and risk-reducing surgeries. The ability to better identify carriers with pathogenic genetic variants associated with gastric cancer before a diagnosis of cancer requires effective genetic risk assessment and testing, followed by optimal screening and surveillance recommendations to further reduce the morbidity and mortality.
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15
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Iyer P, Moslim M, Farma JM, Denlinger CS. Diffuse gastric cancer: histologic, molecular, and genetic basis of disease. Transl Gastroenterol Hepatol 2020; 5:52. [PMID: 33073047 DOI: 10.21037/tgh.2020.01.02] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 01/15/2020] [Indexed: 12/24/2022] Open
Abstract
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. In addition, DGC is associated with familial syndromes, including hereditary DGC and germline mutation in CDH1. Clinically, this subtype of gastric adenocarcinoma is associated with a poor prognosis and possible resistance to available systemic therapies. An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. In this review, we will review the current histologic, molecular, and genetic landscape of DGC and its relevance to clinical practice.
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Affiliation(s)
- Pritish Iyer
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Maitham Moslim
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jeffrey M Farma
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Crystal S Denlinger
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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16
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Predicting Peritoneal Dissemination of Gastric Cancer in the Era of Precision Medicine: Molecular Characterization and Biomarkers. Cancers (Basel) 2020; 12:cancers12082236. [PMID: 32785164 PMCID: PMC7547377 DOI: 10.3390/cancers12082236] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/29/2020] [Accepted: 08/05/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers.
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17
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Lyons K, Le LC, Pham YTH, Borron C, Park JY, Tran CTD, Tran TV, Tran HTT, Vu KT, Do CD, Pelucchi C, La Vecchia C, Zgibor J, Boffetta P, Luu HN. Gastric cancer: epidemiology, biology, and prevention: a mini review. Eur J Cancer Prev 2020; 28:397-412. [PMID: 31386635 DOI: 10.1097/cej.0000000000000480] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric cancer is one of the most common causes of cancer-related mortality worldwide. The objective of this article is to review the epidemiology and biology of gastric cancer risk. This literature review explores the biological, clinical, and environmental factors that influence the rates of this disease and discuss the different intervention methods that may not only increase the awareness of gastric cancer but also increase screening in efforts to reduce the risk of gastric cancer. Helicobacter pylori infection is the primary risk factor for gastric cancer. Additional risk factors include geographical location, age, sex, smoking, socioeconomic status, dietary intake, and genetics. Primary and secondary prevention strategies such as dietary modifications and screenings are important measures for reducing the risk of gastric cancer. Interventions, such as H. pylori eradication through chemoprevention trials, have shown some potential as a preventative strategy. Although knowledge about gastric cancer risk has greatly increased, future research is warranted on the differentiation of gastric cancer epidemiology by subsite and exploring the interactions between H. pylori infection, genetics, and environmental factors. Better understanding of these relationships can help researchers determine the most effective intervention strategies for reducing the risk of this disease.
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Affiliation(s)
- Kiara Lyons
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida
| | - Linh C Le
- VinUniversity Project-Health Sciences.,Vinmec Healthcare System
| | | | - Claire Borron
- Icahn School of Medicine, Mount Sinai School of Medicine, Tisch Cancer Institute, New York City, New York
| | - Jong Y Park
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Chi T D Tran
- Vietnam Colorectal Cancer and Polyp Research Program, Vinmec Healthcare System
| | - Thuan V Tran
- Vietnam National Cancer Hospital.,Vietnam National Cancer Institute
| | - Huong T-T Tran
- Vietnam National Cancer Hospital.,Vietnam National Cancer Institute
| | - Khanh T Vu
- Department of Gastroenterology, Bach Mai Hospital
| | - Cuong D Do
- Department of Infectious Disease, Bach Mai Hospital, Hanoi, Vietnam
| | - Claudio Pelucchi
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Janice Zgibor
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida
| | - Paolo Boffetta
- Icahn School of Medicine, Mount Sinai School of Medicine, Tisch Cancer Institute, New York City, New York
| | - Hung N Luu
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health.,Division of Cancer Control and Population Sciences, Hillman Cancer Canter, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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18
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Caggiari L, Fornasarig M, De Zorzi M, Cannizzaro R, Steffan A, De Re V. Family's History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form. Int J Mol Sci 2020; 21:ijms21144904. [PMID: 32664545 PMCID: PMC7402300 DOI: 10.3390/ijms21144904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/07/2020] [Accepted: 07/09/2020] [Indexed: 11/16/2022] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10-18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.
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Affiliation(s)
- Laura Caggiari
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Mara Fornasarig
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.F.); (R.C.)
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Renato Cannizzaro
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.F.); (R.C.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, Bioproteomic facility, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.C.); (M.D.Z.); (A.S.)
- Correspondence: ; Tel.: +39-0434-659672
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19
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Corso G, Montagna G, Figueiredo J, La Vecchia C, Fumagalli Romario U, Fernandes MS, Seixas S, Roviello F, Trovato C, Guerini-Rocco E, Fusco N, Pravettoni G, Petrocchi S, Rotili A, Massari G, Magnoni F, De Lorenzi F, Bottoni M, Galimberti V, Sanches JM, Calvello M, Seruca R, Bonanni B. Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review. Cancers (Basel) 2020; 12:E1598. [PMID: 32560361 PMCID: PMC7352390 DOI: 10.3390/cancers12061598] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023] Open
Abstract
E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as-(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC).
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Affiliation(s)
- Giovanni Corso
- Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (G.M.); (F.M.); (V.G.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (E.G.-R.); (N.F.); (G.P.)
| | - Giacomo Montagna
- Breast Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Joana Figueiredo
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (J.F.); (M.S.F.); (S.S.); (R.S.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy;
| | - Uberto Fumagalli Romario
- Department of Digestive Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy;
| | - Maria Sofia Fernandes
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (J.F.); (M.S.F.); (S.S.); (R.S.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Susana Seixas
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (J.F.); (M.S.F.); (S.S.); (R.S.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Franco Roviello
- Departments of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy;
| | - Cristina Trovato
- Division of Endoscopy, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy;
| | - Elena Guerini-Rocco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (E.G.-R.); (N.F.); (G.P.)
- Division of Pathology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (E.G.-R.); (N.F.); (G.P.)
- Division of Pathology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy
| | - Gabriella Pravettoni
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy; (E.G.-R.); (N.F.); (G.P.)
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy;
| | - Serena Petrocchi
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy;
| | - Anna Rotili
- Division of Breast Imaging, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy;
| | - Giulia Massari
- Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (G.M.); (F.M.); (V.G.)
| | - Francesca Magnoni
- Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (G.M.); (F.M.); (V.G.)
| | - Francesca De Lorenzi
- Division of Plastic Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (F.D.L.); (M.B.)
| | - Manuela Bottoni
- Division of Plastic Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (F.D.L.); (M.B.)
| | - Viviana Galimberti
- Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (G.M.); (F.M.); (V.G.)
| | - João Miguel Sanches
- Institute for Systems and Robotics, Instituto Superior Técnico, 1049-001 Lisboa, Portugal;
| | - Mariarosaria Calvello
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (M.C.); (B.B.)
| | - Raquel Seruca
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; (J.F.); (M.S.F.); (S.S.); (R.S.)
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
- Medical Faculty, University of Porto, 4099-002 Porto, Portugal
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy; (M.C.); (B.B.)
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20
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CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer. Genes (Basel) 2020; 11:genes11040391. [PMID: 32260281 PMCID: PMC7231129 DOI: 10.3390/genes11040391] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/16/2023] Open
Abstract
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.
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21
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Renaud F, Svrcek M. [Hereditary gastric cancer: Challenges for the pathologist in 2020]. Ann Pathol 2020; 40:95-104. [PMID: 32147190 DOI: 10.1016/j.annpat.2020.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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Affiliation(s)
- Florence Renaud
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
| | - Magali Svrcek
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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22
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Georgopoulos SD, Michopoulos S, Rokkas T, Apostolopoulos P, Giamarellos E, Kamberoglou D, Mentis A, Triantafyllou K. Hellenic consensus on Helicobacter pylori infection. Ann Gastroenterol 2020; 33:105-124. [PMID: 32127732 PMCID: PMC7049243 DOI: 10.20524/aog.2020.0446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/30/2019] [Indexed: 02/06/2023] Open
Abstract
The Hellenic Society of Gastroenterology recently organized the “Hellenic consensus on Helicobacter pylori (H. pylori) infection”. The aim of this publication is to report the guidelines in order to aid the national gastroenterology community in the management of H. pylori infection. Forty-one delegates from all Greek regions, including gastroenterologists, pathologists, clinical microbiologists, epidemiologists and basic scientists, were invited to this meeting. The participants were allocated to 1 of the 4 main topics of the meeting: i.e., H. pylori diagnosis and association with diseases; H. pylori and gastric cancer; H. pylori and extragastric associated disorders; and H. pylori treatment. The results of each subgroup were submitted to a final consensus vote that included all participants. Relevant data based on international and Greek publications were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. The cutoff level of 70% was considered as acceptance for the final statement. It is hoped that the recommendations and conclusions of this report will guide Greek doctors in their daily practice concerning the management of H. pylori infection.
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Affiliation(s)
| | | | - Theodoros Rokkas
- Gastroenterology Department, Henry Dynan Hospital (Theodoros Rokkas)
| | | | - Evangelos Giamarellos
- 4 Department of Internal Medicine, Attikon University Hospital (Evangelos Giamarellos)
| | | | - Andreas Mentis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, (Andreas Mentis)
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23
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Shenoy S. CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management. Cancer Manag Res 2019; 11:10477-10486. [PMID: 31853199 PMCID: PMC6916690 DOI: 10.2147/cmar.s208818] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer. Methods Relevant articles from PubMed/Medline and Embase (1994–2019) were searched and collected using the phrases “Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy”. Results Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy. Conclusion Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.
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Affiliation(s)
- Santosh Shenoy
- Clinical Associate Professor of Surgery, Department of Surgery, Kansas City VA Medical Center, University of Missouri Kansas City, Kansas City, MO 64128, USA and Cancer Biology and Therapeutics, HMS High-Impact Cancer Research (HI-CR) Program, Harvard Medical School 2018-2019, Boston, MA 02115, USA
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24
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Kim N. Chemoprevention of gastric cancer by Helicobacter pylori eradication and its underlying mechanism. J Gastroenterol Hepatol 2019; 34:1287-1295. [PMID: 30828872 DOI: 10.1111/jgh.14646] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/23/2019] [Accepted: 03/01/2019] [Indexed: 12/11/2022]
Abstract
The cascade of gastric cancer, a leading cause of cancer incidence and mortality, is multifactorial. Helicobacter pylori (HP) infection plays a major role in gastric cancer (GC), and there has been an accumulation of data regarding the chemopreventive effect of HP eradication. However, it remains unclear how HP infection causes GC and how HP eradication prevents GC. To clarify this issue, the following approaches were performed in this review article. First, how HP-induced atrophic gastritis (AG) and intestinal metaplasia (IM) provoke the development of GC is shown, followed by how long HP eradication takes to induce a reversible change in AG and IM. Second, epigenetic studies of PTPN6, MOS, DCC, CRK, and VAV1 were performed in noncancerous gastric specimens in terms of HP status. Among these genes, MOS was found to be a possible surrogate marker for GC development. HP eradication decreased aberrant DNA methylation in a gene-specific manner, and MOS played a role in metachronous gastric neoplasms. Third, transforming growth factor-β1 (TGF-β1) and TGF-β1-induced epithelial-mesenchymal transition (EMT) markers were investigated in gastric mucosa. HP infection triggered the TGF-β1-induced EMT pathway and caused the emergence of GC stem cells, such as CD44v8-10. When HP was eradicated, these two pathways were inhibited. Finally, a 2222 cohort study showed that HP eradication significantly decreased the risk of noncardiac GC. Taken together, HP eradication is effective as a primary GC prevention method, and its underlying mechanism includes reversibility of AG and IM, methylation, EMT, and stem cells.
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Affiliation(s)
- Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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25
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Aiello NM, Kang Y. Context-dependent EMT programs in cancer metastasis. J Exp Med 2019; 216:1016-1026. [PMID: 30975895 PMCID: PMC6504222 DOI: 10.1084/jem.20181827] [Citation(s) in RCA: 402] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a developmental process whereby stationary, adherent cells acquire the ability to migrate. EMT is critical for dramatic cellular movements during embryogenesis; however, tumor cells can reactivate EMT programs, which increases their aggressiveness. In addition to motility, EMT is associated with enhanced stem cell properties and drug resistance; thus it can drive metastasis, tumor recurrence, and therapy resistance in the context of cancer. However, the precise requirements for EMT in metastasis have not been fully delineated, with different tumor types relying on discrete EMT effectors. Most tumor cells do not undergo a full EMT, but rather adopt some qualities of mesenchymal cells and maintain some epithelial characteristics. Emerging evidence suggests that partial EMT can drive distinct migratory properties and enhance the epithelial-mesenchymal plasticity of cancer cells as well as cell fate plasticity. This review discusses the diverse regulatory mechanisms and functional consequences of EMT, with an emphasis on the importance of partial EMT.
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Affiliation(s)
- Nicole M Aiello
- Department of Molecular Biology, Princeton University, Princeton, NJ
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ
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26
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Figueiredo J, Melo S, Carneiro P, Moreira AM, Fernandes MS, Ribeiro AS, Guilford P, Paredes J, Seruca R. Clinical spectrum and pleiotropic nature of CDH1 germline mutations. J Med Genet 2019; 56:199-208. [PMID: 30661051 PMCID: PMC6581119 DOI: 10.1136/jmedgenet-2018-105807] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 12/12/2022]
Abstract
CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.
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Affiliation(s)
- Joana Figueiredo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Soraia Melo
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal
| | - Patrícia Carneiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Ana Margarida Moreira
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Maria Sofia Fernandes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.,Institute for Systems and Robotics (ISR/IST), LARSyS, Bioengineering Department, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Sofia Ribeiro
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Joana Paredes
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Raquel Seruca
- Epithelial Interactions in Cancer Department, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Medical Faculty of the University of Porto, Porto, Portugal.,Epithelial Interactions in Cancer, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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27
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Mun DG, Bhin J, Kim S, Kim H, Jung JH, Jung Y, Jang YE, Park JM, Kim H, Jung Y, Lee H, Bae J, Back S, Kim SJ, Kim J, Park H, Li H, Hwang KB, Park YS, Yook JH, Kim BS, Kwon SY, Ryu SW, Park DY, Jeon TY, Kim DH, Lee JH, Han SU, Song KS, Park D, Park JW, Rodriguez H, Kim J, Lee H, Kim KP, Yang EG, Kim HK, Paek E, Lee S, Lee SW, Hwang D. Proteogenomic Characterization of Human Early-Onset Gastric Cancer. Cancer Cell 2019; 35:111-124.e10. [PMID: 30645970 DOI: 10.1016/j.ccell.2018.12.003] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 08/22/2018] [Accepted: 12/10/2018] [Indexed: 02/08/2023]
Abstract
We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Furthermore, integrated clustering of mRNA, protein, phosphorylation, and N-glycosylation data identified four subtypes of diffuse GCs. Distinguishing these subtypes was possible by proteomic data. Four subtypes were associated with proliferation, immune response, metabolism, and invasion, respectively; and associations of the subtypes with immune- and invasion-related pathways were identified mainly by phosphorylation and N-glycosylation data. Therefore, our proteogenomic analysis provides additional information beyond genomic analyses, which can improve understanding of cancer biology and patient stratification in diffuse GCs.
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Affiliation(s)
- Dong-Gi Mun
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Jinhyuk Bhin
- Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 711-873, Republic of Korea; Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
| | - Sangok Kim
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Hyunwoo Kim
- Department of Computer Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea; Research Data Hub Center, Korea Institute of Science and Technology Information, Daejeon 34141, Republic of Korea
| | - Jae Hun Jung
- Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yong-in 446-701, Republic of Korea
| | - Yeonjoo Jung
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Ye Eun Jang
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Jong Moon Park
- Gachon Institute of Pharmaceutical Sciences, Gachon College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea
| | - Hokeun Kim
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Yeonhwa Jung
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Hangyeore Lee
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Jingi Bae
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Seunghoon Back
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Su-Jin Kim
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea
| | - Jieun Kim
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Heejin Park
- Department of Computer Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea
| | - Honglan Li
- School of Computer Science and Engineering, Soongsil University, Seoul 156-743, Republic of Korea
| | - Kyu-Baek Hwang
- School of Computer Science and Engineering, Soongsil University, Seoul 156-743, Republic of Korea
| | - Young Soo Park
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-873, Republic of Korea
| | - Jeong Hwan Yook
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-873, Republic of Korea
| | - Byung Sik Kim
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-873, Republic of Korea
| | - Sun Young Kwon
- Department of Surgery, Keimyung University School of Medicine, Daegu 700-712, Republic of Korea
| | - Seung Wan Ryu
- Department of Surgery, Keimyung University School of Medicine, Daegu 700-712, Republic of Korea
| | - Do Youn Park
- Department of Pathology, Pusan National University School of Medicine, Busan 602-739, Republic of Korea
| | - Tae Yong Jeon
- Department of Surgery, Pusan National University School of Medicine, Busan 602-739, Republic of Korea
| | - Dae Hwan Kim
- Department of Surgery, Pusan National University School of Medicine, Busan 602-739, Republic of Korea
| | - Jae-Hyuck Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon 443-380 Republic of Korea
| | - Kyu Sang Song
- Department of Pathology, School of Medicine, Chungnam National University, Daejeon 301-747 Republic of Korea
| | - Dongmin Park
- National Cancer Center, Goyang 410-769, Republic of Korea
| | - Jun Won Park
- National Cancer Center, Goyang 410-769, Republic of Korea
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jaesang Kim
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Hookeun Lee
- Gachon Institute of Pharmaceutical Sciences, Gachon College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yong-in 446-701, Republic of Korea
| | - Eun Gyeong Yang
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
| | - Hark Kyun Kim
- National Cancer Center, Goyang 410-769, Republic of Korea.
| | - Eunok Paek
- Department of Computer Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
| | - Sanghyuk Lee
- Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 120-750, Republic of Korea.
| | - Sang-Won Lee
- Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul 136-701, Republic of Korea.
| | - Daehee Hwang
- Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 711-873, Republic of Korea.
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28
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Luo W, Fedda F, Lynch P, Tan D. CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment. Front Pharmacol 2018; 9:1421. [PMID: 30568591 PMCID: PMC6290068 DOI: 10.3389/fphar.2018.01421] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes "invasive" in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.
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Affiliation(s)
- Wenyi Luo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Faysal Fedda
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrick Lynch
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dongfeng Tan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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29
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Moslim MA, Heald B, Tu C, Burke CA, Walsh RM. Early genetic counseling and detection of CDH1 mutation in asymptomatic carriers improves survival in hereditary diffuse gastric cancer. Surgery 2018; 164:754-759. [PMID: 30145018 DOI: 10.1016/j.surg.2018.05.059] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/02/2018] [Accepted: 05/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hereditary diffuse gastric cancer is associated with E-cadherin (CDH1) germline mutations. The implications of CDH1 mutations detected with multigene panels in those without family history of HDGC are uncertain. METHODS A registry of patients who underwent genetic counseling for CDH1 mutation was queried for the period 2011-2017. RESULTS Twenty-one patients with CDH1 mutation were identified. The most common indication for CDH1 genetic screening was family history of hereditary diffuse gastric cancer (known risk) in 10 patients (48%); 11 patients (52%), however, were diagnosed by multigene cancer panels (unknown risk). Nine of the 21 patients underwent total gastrectomy, and 5 others had metastatic gastric cancer at presentation. In the gastrectomy group, 5 of the 9 patients (56%) were known to have gastric cancer based on preoperative screening endoscopy, but final pathologic examinations indicated diffuse gastric cancer in 8 of the 9 patients. The 11 patients with unknown risk for CDH1 mutation tended to be older (median 41 vs 24 years) and more likely to have metastatic disease and to die of the disease (43% vs 29%) compared with patients with family history of hereditary diffuse gastric cancer. CONCLUSION CDH1 mutation-associated hereditary diffuse gastric cancer is a biologically aggressive variant of gastric cancer that appears to behave similarly in patients detected only by multigene panels. The detection of CDH1 mutation at a minimum warrants genetic counseling and preferably total gastrectomy.
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Affiliation(s)
- Maitham A Moslim
- Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH
| | - Brandie Heald
- Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH
| | - Chao Tu
- Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH
| | - Carol A Burke
- Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH
| | - R Matthew Walsh
- Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH.
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30
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Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
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31
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Emerging Concepts in Gastric Neoplasia: Heritable Gastric Cancers and Polyposis Disorders. Surg Pathol Clin 2018; 10:931-945. [PMID: 29103540 DOI: 10.1016/j.path.2017.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hereditary gastric cancer is a relatively rare disease with specific clinical and histopathologic characteristics. Hereditary gastric cancer of the diffuse type is predominantly caused by germline mutations in CDH1. The inherited cause of familial intestinal gastric cancer is unknown. Gastric adenocarcinoma and proximal polyposis of the stomach is a hereditary cancer syndrome caused by germline mutations in promoter 1B of APC. Other well-defined cancer syndromes, such as Lynch, Li-Fraumeni, and hereditary breast or ovarian cancer syndromes, are associated with increased risk of gastric cancer. This article reviews important histopathologic features and emerging concepts regarding gastric carcinogenesis in these syndromes.
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32
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Spoto CP, Gullo I, Carneiro F, Montgomery EA, Brosens LA. Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing. Semin Diagn Pathol 2018; 35:170-183. [DOI: 10.1053/j.semdp.2018.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Zylberberg HM, Sultan K, Rubin S. Hereditary diffuse gastric cancer: One family’s story. World J Clin Cases 2018; 6:1-5. [PMID: 29376063 PMCID: PMC5767847 DOI: 10.12998/wjcc.v6.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/08/2017] [Accepted: 12/12/2017] [Indexed: 02/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited form of gastric cancer that carries a poor prognosis. Most HDGCs are caused by an autosomal dominant genetic mutation in the CDH1 gene, which carries a 70%-80% lifetime risk of gastric cancer. Given its submucosal origin, endoscopic surveillance is an unreliable means of early detection, and prophylactic gastrectomy is recommended for CDH1 positive individuals older than age 20 years. We describe the case of a male with recurrent gastric cancer who was diagnosed with HDGC secondary to the CDH1 mutation, and we also describe the patient’s pedigree and outcomes of recommended genetic testing.
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Affiliation(s)
- Haley M Zylberberg
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
| | - Keith Sultan
- Division of Gastroenterology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, United States
| | - Steven Rubin
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Merrick, NY 11566, United States
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Diagnostic, Predictive, Prognostic, and Therapeutic Molecular Biomarkers in Third Millennium: A Breakthrough in Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7869802. [PMID: 29094049 PMCID: PMC5637861 DOI: 10.1155/2017/7869802] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
Introduction Gastric cancer is the fifth most common cancer and the third cause of cancer death. The clinical outcomes of the patients are still not encouraging with a low rate of 5 years' survival. Often the disease is diagnosed at advanced stages and this obviously negatively affects patients outcomes. A deep understanding of molecular basis of gastric cancer can lead to the identification of diagnostic, predictive, prognostic, and therapeutic biomarkers. Main Body This paper aims to give a global view on the molecular classification and mechanisms involved in the development of the tumour and on the biomarkers for gastric cancer. We discuss the role of E-cadherin, HER2, fibroblast growth factor receptor (FGFR), MET, human epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), mammalian target of rapamycin (mTOR), microsatellite instability (MSI), PD-L1, and TP53. We have also considered in this manuscript new emerging biomarkers as matrix metalloproteases (MMPs), microRNAs, and long noncoding RNAs (lncRNAs). Conclusions Identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers will have a huge impact on patients outcomes as they will allow early detection of tumours and also guide the choice of a targeted therapy based on specific molecular features of the cancer.
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36
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Boland CR, Yurgelun MB. Historical Perspective on Familial Gastric Cancer. Cell Mol Gastroenterol Hepatol 2017; 3:192-200. [PMID: 28275686 PMCID: PMC5331778 DOI: 10.1016/j.jcmgh.2016.12.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 12/25/2016] [Indexed: 12/18/2022]
Abstract
Gastric cancer is a common disease worldwide, typically associated with acquired chronic inflammation in the stomach, related in most instances to infection by Helicobacter pylori. A small percentage of cases occurs in familial clusters, and some of these can be linked to specific germline mutations. This article reviews the historical background to the current understanding of familial gastric cancer, focuses on the entity of hereditary diffuse gastric cancer, and also reviews the risks for gastric cancer related to a number of other familial genetic diseases.
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Affiliation(s)
- C. Richard Boland
- Division of GI, University of California San Diego School of Medicine, San Diego, California,Correspondence Address correspondence to: C. Richard Boland, MD, UCSD School of Medicine, San Diego, California 92110.UCSD School of MedicineSan DiegoCalifornia 92110
| | - Matthew B. Yurgelun
- Dana-Farber Cancer Institute, Boston, Massachusetts,Matthew B. Yurgelun, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1126, Boston, Massachusetts 02215. fax: (617) 632–5370.Dana-Farber Cancer Institute450 Brookline AvenueDana 1126BostonMassachusetts 02215
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37
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Zhang C, Min L, Liu J, Tian W, Han Y, Qu L, Shou C. Integrated analysis identified an intestinal-like and a diffuse-like gene sets that predict gastric cancer outcome. Tumour Biol 2016; 37:16317–16335. [PMID: 27858295 DOI: 10.1007/s13277-016-5454-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 09/23/2016] [Indexed: 10/20/2022] Open
Abstract
The two major histological types of gastric cancer, intestinal and diffuse subtypes, have distinct epidemiological and pathophysiological features and were also suggested to be of diverse clinical outcomes. Although the gene expression spectrum of gastric cancer subtypes has been reported by previous studies, its linkage with gastric cancer clinical features and outcomes remains elusive. We investigated large-sample online gastric cancer datasets for seeking genes correlated with the clinical diversities between gastric cancer intestinal and diffuse subtypes. Genes differently expressed between the two subtypes were assessed by multiple statistical analysis and were testified on cellular level by quantitative RT-PCR. Related genes were combined to generate a risk signature, and their mutual linkages were also explored. Among genes overexpressed in intestinal subtype, ATPIF1, PRDX2, PRKAR2A, and SMC1A were correlated with positive prognosis. Among genes overexpressed in diffuse subtype, DTNA, GPR161, IDS, RHOQ, and TSHZ2 were correlated with negative prognosis. These nine genes were all novel independent prognostic factors. When used in combination as signatures, these two gene sets displayed strong efficacy for prediction of the prognosis and clinical variables in gastric and colorectal cancer. Hence, these two genes sets were respectively defined as the favorable intestinal-like and adverse diffuse-like gene sets. We identified nine novel genes correlated with the clinical diversity between the intestinal and diffuse subtypes of gastric cancer. The malignant changes from the intestinal to diffuse subtype might be due to the reduction of the four intestinal-like genes, as well as the elevation of the five diffuse-like genes.
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Affiliation(s)
- Cheng Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Li Min
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Jiafei Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Wei Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Cancer Etiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yong Han
- Department of Pathology, Zhejiang Provincial People's Hospital, Zhejiang, 310014, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
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Pantelis D, Hüneburg R, Adam R, Holzapfel S, Gevensleben H, Nattermann J, Strassburg CP, Aretz S, Kalff JC. Prophylactic total gastrectomy in the management of hereditary tumor syndromes. Int J Colorectal Dis 2016; 31:1825-1833. [PMID: 27682646 DOI: 10.1007/s00384-016-2656-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/19/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE Germline mutations in several genes confer a relevant lifetime risk of gastric cancer. In this context, an increasing involvement of a surgeon can be seen, mainly with the question of performing a prophylactic operation. METHODS Patients with hereditary tumor syndromes predisposing for gastric cancer who received care leading to prophylactic total gastrectomy in our Center for Hereditary Tumor Syndromes were analyzed. For each patient, the multidisciplinary decision-making process, the perioperative course, and the histopathologic findings were assessed. Short-term morbidity was evaluated based on the medical reports. RESULTS The analysis includes nine patients (six female, three male) with a median age of 41.6 (range 23-60) years. Indication for prophylactic total gastrectomy was based on family history and genetic analysis (eight patients with a germline mutation of the CDH1 gene and one patient with a SMAD4 mutation). Removal of the entire gastric mucosa was documented intraoperatively by fresh frozen section examination. Extended (DII) lymphadenectomy was performed in four patients. Histopathologic examination of gastrectomy specimens revealed six patients (6/9, 67 %) with multifocal signet ring cell carcinomas. In our series, prophylactic total gastrectomy was a safe procedure without mortality and low morbidity. CONCLUSIONS Patients with hereditary syndromes predisposing for gastric cancer should be evaluated for this curative procedure in a specialized center. Further research is necessary, and the implementation of nationwide registers including patients with prophylactic gastrointestinal operations due to hereditary tumor syndrome is advisable.
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Affiliation(s)
- Dimitrios Pantelis
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital of Bonn, Bonn, Germany. .,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
| | - Robert Hüneburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Ronja Adam
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
| | - Stefanie Holzapfel
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
| | - Heidrun Gevensleben
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - Jacob Nattermann
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Christian P Strassburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
| | - Stefan Aretz
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
| | - Jörg C Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
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Oh S, Kim N, Kwon JW, Shin CM, Choi YJ, Lee DH, Jung HC. Effect of Helicobacter pylori Eradication and ABO Genotype on Gastric Cancer Development. Helicobacter 2016; 21:596-605. [PMID: 27191536 DOI: 10.1111/hel.12317] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Evidence is lacking regarding how Helicobacter pylori infection status, eradication history, and ABO blood type affect the development of gastric cancer (GC) given the multifactorial and distinctive etiology according to cancer location (noncardia vs cardia) and histologic type (intestinal vs diffuse-type). We evaluated the effect of H. pylori infection status incorporated with H. pylori eradication history and ABO genotype on GC development according to cancer location and histologic type. METHODS A case-control study of 997 patients with noncardia GC (NCGC) and 1147 control subjects was performed using risk analyses with 14 factors including H. pylori infection with eradication history and ABO genotype. As final analyses, multivariable logistic regression models were fitted. Additionally, H. pylori infection status with eradication history was tested for its association with age, atrophic gastritis (AG), and intestinal metaplasia (IM). RESULTS The ABO genotype with the B allele was associated with a significantly lower risk of NCGC of both histologic types. The reduction in risk for NCGC by adding the B allele was more prominent in diffuse-type than that in the intestinal-type. H. pylori infection with eradication history was associated with a significantly lower risk of NCGC of both histologic types, compared with those without eradication history (odds ratio (OR), 0.22; 95% confidence interval (CI), 0.14-0.34) approaching that of uninfected subjects. Past infection status without an eradication history was associated with older age, AG, and IM. CONCLUSIONS H. pylori eradication and the B allele decreased the risks of the intestinal and diffuse-types of NCGC. H. pylori eradication revealed a strong association against developing NCGC. Therefore, it should be considered as a primary measure in NCGC prevention.
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Affiliation(s)
- Sooyeon Oh
- Department of Internal Medicine and Liver Research Institute, Seoul National University, College of Medicine, Seoul, Korea
| | - Nayoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University, College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jin-Won Kwon
- College of Pharmacy and Research, Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University, College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University, College of Medicine, Seoul, Korea
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Jia Y, Cao B, Yang Y, Linghu E, Zhan Q, Lu Y, Yu Y, Herman JG, Guo M. Silencing NKD2 by promoter region hypermethylation promotes gastric cancer invasion and metastasis by up-regulating SOX18 in human gastric cancer. Oncotarget 2016; 6:33470-85. [PMID: 26396173 PMCID: PMC4741779 DOI: 10.18632/oncotarget.5272] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 09/02/2015] [Indexed: 12/26/2022] Open
Abstract
Naked cuticle homolog2 (NKD2) is located in chromosome 5p15.3, which is frequently loss of heterozygosity in human colorectal and gastric cancers. In order to understand the mechanism of NKD2 in gastric cancer development, 6 gastric cancer cell lines and 196 cases of human primary gastric cancer samples were involved. Methylation specific PCR (MSP), gene expression array, flow cytometry, transwell assay and xenograft mice model were employed in this study. The expression of NKD1 and NKD2 was silenced by promoter region hypermethylation. NKD1 and NKD2 were methylated in 11.7% (23/196) and 53.1% (104/196) in human primary gastric cancer samples. NKD2 methylation is associated with cell differentiation, TNM stage and distant metastasis significantly (all P < 0.05), and the overall survival time is longer in NKD2 unmethylated group compared to NKD2 methylated group (P < 0.05). Restoration of NKD2 expression suppressed cell proliferation, colony formation, cell invasion and migration, induced G2/M phase arrest, and sensitized cancer cells to docetaxel. NKD2 inhibits SOX18 and MMP-2,7,9 expression and suppresses BGC823 cell xenograft growth. In conclusion, NKD2 methylation may serve as a poor prognostic and chemo-sensitive marker in human gastric cancer. NKD2 impedes gastric cancer metastasis by inhibiting SOX18.
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Affiliation(s)
- Yan Jia
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China.,Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, and Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Baoping Cao
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China.,Medical College of NanKai University, Tianjin 300071, China
| | - Yunsheng Yang
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Enqiang Linghu
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Qimin Zhan
- State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Youyong Lu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, Beijing 100142, China
| | - Yingyan Yu
- Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China
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41
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Alkebsi L, Handa H, Yokohama A, Saitoh T, Tsukamoto N, Murakami H. Chromosome 16q genes CDH1, CDH13 and ADAMTS18 are correlated and frequently methylated in human lymphoma. Oncol Lett 2016; 12:3523-3530. [PMID: 27900031 DOI: 10.3892/ol.2016.5116] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/19/2016] [Indexed: 12/31/2022] Open
Abstract
The products of the E-cadherin (CDH1), H-cadherin (CDH13) and a disintegrin and metalloproteinase with thrombospondin motif 18 (ADAMTS18) genes are proteins displaying structural features and functions on the cell surface membrane, and have been reported to be involved in cancer progression. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and methylation-specific PCR (MSP) analysis, the promoter methylation status and messenger RNA (mRNA) expression levels of CDH1, CDH13 and ADAMTS18, which are putative tumor-suppressor genes located on chromosome 16q, were evaluated. In addition, the mRNA expression levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were examined, and the correlations among the different parameters analyzed were studied in 36 lymphomas and 16 non-malignant lymphoid tissue samples. A significant positive correlation was identified between the expression levels of CDH1 and CDH13 (r=0.735, P<0.01). ADAMTS18 expression also exhibited a significant positive correlation with both CDH1 and CDH13 mRNA expression levels (r=0.625, P<0.01; and r=0.720, P<0.01, respectively). Our results indicated that CDH1, CDH13 and ADAMTS18, which are localized on chromosome 16q, are remarkably correlated and frequently methylated in human lymphomas, and their methylation could not be explained solely by the mRNA expression level of DNMTs.
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Affiliation(s)
- Lobna Alkebsi
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Gunma 371-8511, Japan
| | - Hiroshi Handa
- Department of Medicine and Clinical Sciences, Graduate School of Medicine, Gunma University Hospital, Gunma 371-8511, Japan
| | - Akihiko Yokohama
- Blood Transfusion Service, Gunma University Hospital, Gunma 371-8511, Japan
| | - Takayuki Saitoh
- Oncology Center, Gunma University Hospital, Gunma 371-8511, Japan
| | | | - Hirokazu Murakami
- Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Gunma 371-8511, Japan
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Abstract
Gastric cancer (GC) is third leading cause of cancer-related death. Only 28.3% of new GC cases survive more than 5 years. Although incidence has declined in the United States, an increase is estimated for 2016. Risk factors include sex (risk is higher in men), Helicobacter pylori infection, heredity, and lifestyle. GC is usually diagnosed between the ages of 60-80 years. Prognosis of GC is largely dependent on the tumor stage at diagnosis and classification as intestinal or diffuse type; diffuse-type GC has worse prognosis. Chemoprevention has been shown to decrease risk, but is currently not used clinically.
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Affiliation(s)
- Juan M Marqués-Lespier
- Division of Gastroenterology, Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR 00935, USA
| | - María González-Pons
- University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00935, USA
| | - Marcia Cruz-Correa
- Departments of Medicine, Surgery, and Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00935, USA.
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Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
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Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
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Poh AR, O'Donoghue RJJ, Ernst M, Putoczki TL. Mouse models for gastric cancer: Matching models to biological questions. J Gastroenterol Hepatol 2016; 31:1257-72. [PMID: 26809278 PMCID: PMC5324706 DOI: 10.1111/jgh.13297] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.
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Affiliation(s)
- Ashleigh R Poh
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| | - Robert J J O'Donoghue
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Matthias Ernst
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Tracy L Putoczki
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
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Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-74. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
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Li Y, Ran R, Guan Y, Zhu X, Kang S. Aberrant Methylation of the E-Cadherin Gene Promoter Region in the Endometrium of Women With Uterine Fibroids. Reprod Sci 2016; 23:1096-102. [DOI: 10.1177/1933719116630415] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Yan Li
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, China
| | - Ran Ran
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, China
| | - Yingxia Guan
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiong Zhu
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, China
| | - Shan Kang
- Department of Gynecology, Fourth Hospital, Hebei Medical University, Shijiazhuang, China
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Abstract
A positive family history is consistently reported as a risk factor for gastric cancer (GC), but the molecular basis for the familial aggregation is largely unknown. The risk associated with having one first-degree relative (FDR) with GC is approximately 1.3-3.5 fold increased. Hereditary cancer syndromes have been relatively well characterised, but their rarity largely precludes the development of trials of surveillance. In hereditary diffuse gastric cancer (HDGC), patients have a CDH1 mutation that results in a high penetrance of GC meaning that prophylactic gastrectomy is recommended, although this treatment results in significant psychosocial issues. The management of HDGC patients includes endoscopic surveillance, surgery and histological interpretation which require a high degree of selective expertise. Much of the remaining heritable risk of GC may be accounted for by low- and intermediate-penetrant genetic factors, i.e. common and rare variants, respectively. The advent of new methods such as next-generation sequencing has revealed a number of new candidate gene loci.
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Affiliation(s)
- Kevin John Monahan
- Family History of Bowel Cancer Clinic, Gastroenterology Department, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK.
| | - Laura Hopkins
- Family History of Bowel Cancer Clinic, Gastroenterology Department, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK
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48
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van der Post RS, Gullo I, Oliveira C, Tang LH, Grabsch HI, O'Donovan M, Fitzgerald RC, van Krieken H, Carneiro F. Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:371-91. [PMID: 27573781 DOI: 10.1007/978-3-319-41388-4_18] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.
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Affiliation(s)
- Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal
| | - Carla Oliveira
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
| | - Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA
| | - Heike I Grabsch
- GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Centre, Peter Debyelaan 25, Maastricht, 6229 HX, The Netherlands
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, 197, Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Han van Krieken
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal.
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Abstract
Gastric cancer is one of the most commonly diagnosed and the second leading cause of cancer death worldwide. Surgery combined with multimodal therapy remains the only curative therapy. However, local relapse or distant metastases occur in more than 50% of radically resected patients. Due to molecular therapies, targeting HER2 and angiogenesis, major advances in the treatment of gastric cancer could be achieved. Nevertheless, development of resistance to monoclonal antibodies, such as trastuzumab, is arising. Currently a number of promising new therapeutic are under investigation, combining chemotherapy with newly developed agents to overcome cancer resistance. In this review we report current clinical applications of targeted therapies and overview ongoing trials, investigating the use of monoclonal antibodies in (HER2 positive) gastric cancer.
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Affiliation(s)
- G Jomrich
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
| | - S F Schoppmann
- a Department of Surgery, Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC) , Medical University of Vienna , Vienna , Austria
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50
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Tan RYC, Ngeow J. Hereditary diffuse gastric cancer: What the clinician should know. World J Gastrointest Oncol 2015; 7:153-160. [PMID: 26380059 PMCID: PMC4569593 DOI: 10.4251/wjgo.v7.i9.153] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 08/05/2015] [Indexed: 02/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.
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