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Files R, Cardoso C, Prada J, Silva F, Pires I. Syndecan-1 and E-Cadherin Expression in Canine Cutaneous Squamous Cell Carcinoma. Vet Sci 2024; 11:652. [PMID: 39728992 DOI: 10.3390/vetsci11120652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) in dogs is a locally invasive tumor that typically occurs in areas of poorly pigmented skin due to sun exposure. Identifying new biomarkers, such as syndecan-1 (CD138) and E-cadherin, is fundamental for tumor diagnosis and prognosis. Dysregulation of syndecan-1, expressed in epithelial tissue, fibroblasts, and plasma cells, is associated with poor prognosis in several types of cancer. Similarly, E-cadherin, which plays a crucial role in cell adhesion and epithelial functionality, is also linked to adverse outcomes. This study evaluated the expression of syndecan-1 and E-cadherin in 47 cases of canine cutaneous squamous cell carcinoma. The results showed that the intensity of syndecan-1 decreased with increasing tumor aggressiveness, and its presence in the stroma was significantly associated with tumor grade. E-cadherin also demonstrated a decrease in intensity with increasing malignancy. However, the association between syndecan-1 and E-cadherin was not statistically significant. E-cadherin reduction and stromal syndecan-1 positivity seem to be associated with tumor aggressiveness in canine cutaneous squamous cell carcinoma. Further studies are needed to explore their roles in tumor progression.
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Affiliation(s)
- Rita Files
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Cláudia Cardoso
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Justina Prada
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Filipe Silva
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Isabel Pires
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Animal and Veterinary Research Centre (CECAV), Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
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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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Monster JL, Kemp LJ, Busslinger GA, Vliem MJ, Derks LL, Staes AA, Bisseling TM, Clevers H, van der Post RS, Gloerich M. Cell division-dependent dissemination following E-cadherin loss underlies initiation of diffuse-type gastric cancer. J Pathol 2024; 263:226-241. [PMID: 38572612 DOI: 10.1002/path.6277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/04/2024] [Accepted: 02/22/2024] [Indexed: 04/05/2024]
Abstract
Loss of the cell-cell adhesion protein E-cadherin underlies the development of diffuse-type gastric cancer (DGC), which is characterized by the gradual accumulation of tumor cells originating from the gastric epithelium in the surrounding stroma. How E-cadherin deficiency drives DGC formation remains elusive. Therefore, we investigated the consequences of E-cadherin loss on gastric epithelial organization utilizing a human gastric organoid model and histological analyses of early-stage DGC lesions. E-cadherin depletion from gastric organoids recapitulates DGC initiation, with progressive loss of a single-layered architecture and detachment of individual cells. We found that E-cadherin deficiency in gastric epithelia does not lead to a general loss of epithelial cohesion but disrupts the spindle orientation machinery. This leads to a loss of planar cell division orientation and, consequently, daughter cells are positioned outside of the gastric epithelial layer. Although basally delaminated cells fail to detach and instead reintegrate into the epithelium, apically mispositioned daughter cells can trigger the gradual loss of the single-layered epithelial architecture. This impaired architecture hampers reintegration of mispositioned daughter cells and enables basally delaminated cells to disseminate into the surrounding matrix. Taken together, our findings describe how E-cadherin deficiency disrupts gastric epithelial architecture through displacement of dividing cells and provide new insights in the onset of DGC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jooske L Monster
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Lars Js Kemp
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Georg A Busslinger
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marjolein J Vliem
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Lucca Lm Derks
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Annelot Al Staes
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
| | - Tanya M Bisseling
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn Gloerich
- Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
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Lin J, Chen ZF, Guo GD, Chen X. Impact of Alcian blue and periodic acid Schiff expression on the prognosis of gastric signet ring cell carcinoma. World J Gastrointest Oncol 2024; 16:687-698. [PMID: 38577442 PMCID: PMC10989384 DOI: 10.4251/wjgo.v16.i3.687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/27/2023] [Accepted: 02/06/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND The Alcian blue (AB) and periodic acid Schiff (PAS) stains are representative mucus markers in gastric signet ring cell carcinoma (SRCC). They are low-cost special staining methods used to detect acidic mucus and neutral mucus, respectively. However, the clinical importance of the special combined AB and PAS stain is unclear. AIM To investigate AB expression, PAS expression and the AB-to-PAS (A/P) ratio in gastric SRCC patients and to assess patient prognosis. METHODS Paraffin-embedded sections from 83 patients with gastric SRCC were stained with AB and PAS, and signet ring cell positivity was assessed quantitatively. Immunohistochemical staining for Ki67, protein 53 (P53) and human epidermal growth factor receptor 2 (HER2) was performed simultaneously. The cancer-specific survival (CSS) rate was estimated via Kaplan-Meier analysis. Cox proportional hazards models were used for univariate and multivariate survival analyses. RESULTS Kaplan-Meier survival analysis revealed that the 3-year CSS rate was significantly greater in the high-PAS-expression subgroup than in the low-PAS-expression subgroup (P < 0.001). The 3-year CSS rate in the A/P ≤ 0.5 group was significantly greater than that in the A/P > 0.5 group (P = 0.042). Univariate Cox regression analysis revealed that the factors affecting prognosis included tumor diameter, lymph node metastasis, vessel carcinoma embolus, tumor stage, the A/P ratio and the expression of Ki67, P53 and the PAS. Cox multivariate regression analysis confirmed that low PAS expression [hazard ratio (HR) = 3.809, 95% confidence interval (CI): 1.563-9.283, P = 0.003] and large tumor diameter (HR = 2.761, 95%CI: 1.086-7.020, P = 0.033) were independent risk factors for poor prognosis. CONCLUSION A/P > 0.5 is potentially a risk factor for prognosis, and low PAS expression is an independent risk factor in the prognosis of gastric SRCC. PAS expression and the A/P ratio could help in predicting the clinical prognosis of patients with SRCC.
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Affiliation(s)
- Juan Lin
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian Province, China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China
| | - Zhu-Feng Chen
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian Province, China
- Department of Internal Medicine, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China
| | - Guo-Dong Guo
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian Province, China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China
| | - Xin Chen
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian Province, China
- Department of Pathology, Fujian Provincial Hospital, Fuzhou 350001, Fujian Province, China
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Cai HQ, Zhang LY, Fu LM, Xu B, Jiao Y. Mutational landscape of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg 2024; 16:276-283. [PMID: 38463349 PMCID: PMC10921187 DOI: 10.4240/wjgs.v16.i2.276] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 12/26/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg. A common gene mutation in gastric cancer (GC) is the TP53 mutation. As a tumor suppressor gene, TP53 is implicated in more than half of all tumor occurrences. TP53 gene mutations in GC tissue may be related with clinical pathological aspects. The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy. CDH1 encodes E-cadherin, which is involved in cell-to-cell adhesion, epithelial structure maintenance, cell polarity, differentiation, and intracellular signaling pathway modulation. CDH1 mutations and functional loss can result in diffuse GC, and CDH1 mutations can serve as independent prognostic indicators for poor prognosis. GC patients can benefit from genetic counseling and testing for CDH1 mutations. Demethylation therapy may assist to postpone the onset and progression of GC. The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations, as well as providing some basis for evaluating the prognosis of GC patients.
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Affiliation(s)
- Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Yue Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Ming Fu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bin Xu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Díaz Del Arco C, Fernández Aceñero MJ, Ortega Medina L. Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration. Int J Mol Sci 2024; 25:2649. [PMID: 38473896 DOI: 10.3390/ijms25052649] [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: 01/11/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Gastric cancer (GC) is a heterogeneous disease, often diagnosed at advanced stages, with a 5-year survival rate of approximately 20%. Despite notable technological advancements in cancer research over the past decades, their impact on GC management and outcomes has been limited. Numerous molecular alterations have been identified in GC, leading to various molecular classifications, such as those developed by The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG). Other authors have proposed alternative perspectives, including immune, proteomic, or epigenetic-based classifications. However, molecular stratification has not yet transitioned into clinical practice for GC, and little attention has been paid to alternative molecular classifications. In this review, we explore diverse molecular classifications in GC from a practical point of view, emphasizing their relationships with clinicopathological factors, prognosis, and therapeutic approaches. We have focused on classifications beyond those of TCGA and the ACRG, which have been less extensively reviewed previously. Additionally, we discuss the challenges that must be overcome to ensure their impact on patient treatment and prognosis. This review aims to serve as a practical framework to understand the molecular landscape of GC, facilitate the development of consensus molecular categories, and guide the design of innovative molecular studies in the field.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Luis Ortega Medina
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Xiao J, Li H, Xue F, Luo Z, Pang Y. Prenatal diagnosis of hereditary diffuse gastric cancer: a case report. BMC Pregnancy Childbirth 2023; 23:488. [PMID: 37393258 PMCID: PMC10314645 DOI: 10.1186/s12884-023-05772-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 06/09/2023] [Indexed: 07/03/2023] Open
Abstract
BACKGROUND Hereditary diffuse gastric cancer(HDGC) is a kind of malignant gastric cancer that is difficult to find in the early stage. However, this late onset and incomplete penetrance hereditary cancer, and its prenatal diagnosis have rarely been reported previously. CASE PRESENTATION A 26-year-old woman was referred to genetic counseling for an ultrasonography of fetal choroid plexus cyst at 17 weeks of gestation. The ultrasonographic evaluation showed bilateral choroid plexus cysts(CPC) in the lateral ventricles, and the women showed a family history of gastric cancer and breast cancer. Trio copy number sequencing identified a pathogenic CDH1 deletion in the fetus and unaffected mother. The CDH1 deletion was found in three of the five family members tested, segregation among affected family members. The couple finally decided to terminate the pregnancy after genetic counseling by hospital geneticists due to the uncertainty of the occurrence of HDGC in the future. CONCLUSIONS In prenatal diagnosis, a family history of cancer should be widely concerned, and prenatal diagnosis of hereditary tumors requires extensive cooperation between the prenatal diagnosis structure and the pathology department.
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Affiliation(s)
- Jun Xiao
- College of Traditional Chinese Medicine, Hainan Medical University; Department of Pathology, The First Affiliated Hospital of Hainan Medical University, 570100 Haikou, China
| | - Hui Li
- Prenatal Diagnosis Center, Hainan Maternity and Child Health Hospital, 570100 Haikou, China
| | - Fenggui Xue
- College of Traditional Chinese Medicine, Hainan Medical University; Department of Pathology, The First Affiliated Hospital of Hainan Medical University, 570100 Haikou, China
| | - Zhifei Luo
- College of Traditional Chinese Medicine, Hainan Medical University, 570100 Haikou, China
| | - Yanyang Pang
- College of Traditional Chinese Medicine, Hainan Medical University; Department of Pathology, The First Affiliated Hospital of Hainan Medical University, 570100 Haikou, China
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Alvizi L, Nani D, Brito LA, Kobayashi GS, Passos-Bueno MR, Mayor R. Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction. Nat Commun 2023; 14:2868. [PMID: 37225711 PMCID: PMC10209087 DOI: 10.1038/s41467-023-38526-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 05/05/2023] [Indexed: 05/26/2023] Open
Abstract
Gene-environment interactions are believed to play a role in multifactorial phenotypes, although poorly described mechanistically. Cleft lip/palate (CLP), the most common craniofacial malformation, has been associated with both genetic and environmental factors, with little gene-environment interaction experimentally demonstrated. Here, we study CLP families harbouring CDH1/E-Cadherin variants with incomplete penetrance and we explore the association of pro-inflammatory conditions to CLP. By studying neural crest (NC) from mouse, Xenopus and humans, we show that CLP can be explained by a 2-hit model, where NC migration is impaired by a combination of genetic (CDH1 loss-of-function) and environmental (pro-inflammatory activation) factors, leading to CLP. Finally, using in vivo targeted methylation assays, we demonstrate that CDH1 hypermethylation is the major target of the pro-inflammatory response, and a direct regulator of E-cadherin levels and NC migration. These results unveil a gene-environment interaction during craniofacial development and provide a 2-hit mechanism to explain cleft lip/palate aetiology.
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Affiliation(s)
- Lucas Alvizi
- Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
| | - Diogo Nani
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Luciano Abreu Brito
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Gerson Shigeru Kobayashi
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Maria Rita Passos-Bueno
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil.
| | - Roberto Mayor
- Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.
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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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Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221083049. [PMID: 35281349 PMCID: PMC8908406 DOI: 10.1177/17588359221083049] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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11
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Kheirollahi M, Seyed Tabaei S, Vishteh M, Zeinalian M, Mamaghani A, Zolfaghari M, Mirzapour A, Barati M. Methylation and polymorphism in CDH1 gene promoter among patients with diffuse gastric cancer. Int J Prev Med 2022; 13:44. [PMID: 35529508 PMCID: PMC9069152 DOI: 10.4103/ijpvm.ijpvm_288_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background: The promoter methylation and single nucleotide polymorphisms (SNPs) affect the transcription activity of cancer-related genes in several cancers including diffuse gastric cancer (DGC). Here we aimed to evaluate the promoter methylation status and the rs16260 at the promoter region of the CDH1 gene in DGC. Methods: This case-control study was performed of 48 formalin-fixed paraffin-embedded (FFPE) blocks of DGC patients and 41 fresh frozen tissue samples of healthy individuals. Methylation status was evaluated using methylation-specific polymerase chain reaction (PCR) and the rs16260 at the promoter region of the CDH1 gene was assessed using PCR and sequencing method. Results: The occurrence of methylation at the promoter region of the CDH1 gene in DGC patients was significantly higher than control samples (P < 0.0001). The methylated status was significantly associated with the poor differentiated histological type of DGC (P = 0.0428). The frequency of AC genotype and the A allele in DGC patients was significantly higher than the control subjects (P = 0.006 and 0.003, respectively). Conclusions: Here we showed that methylation at the CDH1 promoter may contribute to the DGC development, and also the AC genotype was associated with the risk of DGC.
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Abstract
E-cadherin is the main component of epithelial adherens junctions (AJs), which play a crucial role in the maintenance of stable cell-cell adhesion and overall tissue integrity. Down-regulation of E-cadherin expression has been found in many carcinomas, and loss of E-cadherin is generally associated with poor prognosis in patients. During the last decade, however, numerous studies have shown that E-cadherin is essential for several aspects of cancer cell biology that contribute to cancer progression, most importantly, active cell migration. In this review, we summarize the available data about the input of E-cadherin in cancer progression, focusing on the latest advances in the research of the various roles E-cadherin-based AJs play in cancer cell dissemination. The review also touches upon the "cadherin switching" in cancer cells where N- or P-cadherin replace or are co-expressed with E-cadherin and its influence on the migratory properties of cancer cells.
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Affiliation(s)
- Svetlana N Rubtsova
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
| | - Irina Y Zhitnyak
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
| | - Natalya A Gloushankova
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
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Sremac M, Paic F, Grubelic Ravic K, Serman L, Pavicic Dujmovic A, Brcic I, Krznaric Z, Nikuseva Martic T. Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma. Oncol Lett 2021; 22:822. [PMID: 34691249 PMCID: PMC8527567 DOI: 10.3892/ol.2021.13083] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Diffuse gastric carcinoma (DGC) is characterized by poorly cohesive cells, highly invasive growth patterns, poor prognosis and resistance to the majority of available systemic therapeutic strategies. It has been previously reported that the Wnt/β-catenin signaling pathway serves a prominent role in the tumorigenesis of gastric carcinoma. However, the mechanism underlying the dysregulation of this pathway in DGC has not been fully elucidated. Therefore, the present study aimed to investigate the expression profiles of Wnt antagonists, secreted frizzled-related protein 1 (SFRP1) and secreted frizzled-related protein 3 (SFRP3), and dishevelled protein family members, dishevelled segment polarity protein 2 (DVL2) and dishevelled segment polarity protein 3 (DVL3), in DGC tissues. The association between the expression levels of these factors and the clinicopathological parameters of the patients was determined. Protein and mRNA expression levels in 62 DGC tumor tissues and 62 normal gastric mucosal tissues obtained from patients with non-malignant disease were measured using immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) analysis. Significantly lower protein expression levels of SFRP1 (P<0.001) and SFRP3 (P<0.001), but significantly higher protein expression levels of DVL2 (P<0.001) and DVL3 (P<0.001) were observed in DGC tissues compared with in control tissues by immunohistochemistry. In addition, significantly lower expression levels of SFRP1 (P<0.05) and higher expression levels of DVL3 (P<0.05) were found in in DGC tissues compared with those in normal gastric mucosal tissues using RT-qPCR. According to correlation analysis between the SFRP1, SFRP3, DVL2 and DVL3 protein expression levels and the clinicopathological characteristics of patients with DGC, a statistically significant correlation was found between the SFRP3 volume density and T stage (r=0.304; P=0.017) and between the SFRP3 volume density and clinical stage (r=0.336; P=0.008). In conclusion, the findings of the present study suggested that the Wnt signaling pathway components SFRP1, SFRP3, DVL2 and DVL3 may be aberrantly expressed in DGC tissues, implicating their possible role in the development of this malignant disease. The present data also revealed a positive relationship between SFRP3 protein expression and the clinical and T stage of DGC.
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Affiliation(s)
- Maja Sremac
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Frane Paic
- Laboratory for Epigenetics and Molecular Medicine, Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Katja Grubelic Ravic
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Ljiljana Serman
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Aja Pavicic Dujmovic
- Department of Radiology, General Hospital 'Dr. Ivo Pedisic', 44000 Sisak, Croatia
| | - Iva Brcic
- Diagnostic and Research Institute of Pathology, Medical University of Graz, A-8010 Graz, Austria
| | - Zeljko Krznaric
- Division of Gastroenterology and Hepatology, University Hospital Center, 10000 Zagreb, Croatia
| | - Tamara Nikuseva Martic
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.,Centre of Excellence in Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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14
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Nikaido M, Kakiuchi N, Miyamoto S, Hirano T, Takeuchi Y, Funakoshi T, Yokoyama A, Ogasawara T, Yamamoto Y, Yamada A, Setoyama T, Shimizu T, Kato Y, Uose S, Sakurai T, Minamiguchi S, Obama K, Sakai Y, Muto M, Chiba T, Ogawa S, Seno H. Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations. Gastric Cancer 2021; 24:1102-1114. [PMID: 33961152 DOI: 10.1007/s10120-021-01191-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
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Affiliation(s)
- Mitsuhiro Nikaido
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan
| | - Shin'ichi Miyamoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .,Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa-Mukaihata-Cho, Fushimi, Kyoto, 612-8555, Japan.
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan
| | - Yasuhide Takeuchi
- Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Taro Funakoshi
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akira Yokoyama
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tatsuki Ogasawara
- Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan
| | - Yoshihiro Yamamoto
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Yamada
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Setoyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Gastroenterology, Osaka Red Cross Hospital, Osaka, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yukari Kato
- Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan
| | - Suguru Uose
- Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan
| | - Takaki Sakurai
- Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Pathology, Kansai Electric Power Hospital, Osaka, Japan
| | - Sachiko Minamiguchi
- Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazutaka Obama
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Surgery, Osaka Red Cross Hospital, Osaka, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan.,Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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15
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Zhao H, Hu H, Chen B, Xu W, Zhao J, Huang C, Xing Y, Lv H, Nie C, Wang J, He Y, Wang SQ, Chen XB. Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications. Front Mol Biosci 2021; 8:689139. [PMID: 34422902 PMCID: PMC8371966 DOI: 10.3389/fmolb.2021.689139] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/19/2021] [Indexed: 01/04/2023] Open
Abstract
Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.
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Affiliation(s)
- Huichen Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huihui Hu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Chen Huang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yishu Xing
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Xiao-Bing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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16
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Ithurralde-Argerich J, Rosner L, Rizzolo M, Faerberg A, Puma R, Ferro D, Duque C, Kujaruk M, Cuenca-Abente F. Laparoscopic Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer in CDH1 Mutation Carriers. J Laparoendosc Adv Surg Tech A 2021; 31:729-737. [PMID: 34097461 DOI: 10.1089/lap.2021.0239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background: Patients with hereditary diffuse gastric cancer (HDGC) and germline mutations in the E-cadherin gene, CDH1, have a very high cumulative lifetime risk of developing diffuse gastric cancer. In these patients, it is formally recommended to perform a prophylactic total gastrectomy (PTG). Materials and Methods: We analyzed the course of patients with HDGC who have undergone PTG in our institution. Pedigree analysis, preoperative screening results, operative course, postoperative data, and complete stomach pathologic examination were performed in all patients. Results: Seven patients with confirmed CDH1 mutation underwent PTG, five were women, and average age was 27 years (range 17-42). Signet ring cell carcinoma was found in 1 patient in the preoperative surveillance endoscopic biopsies. Laparoscopic PTG was performed in all patients. There were two complications, an intestinal obstruction that required reintervention and an asymptomatic esophagojejunal anastomosis leak that resolved with conservative treatment. In all gastrectomy specimens, intramucosal signet ring cell carcinoma foci limited to the lamina propria were found (range 1-31), 83.5% were in the body-fundus region. The mean follow-up was 28.5 months (range 8-72). The mean weight loss was 9% (range 2-18). Postoperative symptoms associated with Dumping syndrome were the most frequent. All the patients reported of being very satisfied with the procedure and of having a better quality of life than expected before the procedure. Conclusion: Laparoscopic PTG is an excellent resource to prevent the development of advanced diffuse gastric cancer (DGC) in patients with HDGC with CDH1 mutation. The procedure was well tolerated with a high satisfaction rate and very good functional results. It should be considered in these patients due to the high risk of developing advanced DGC and the lack of effective and reliable surveillance studies.
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Affiliation(s)
- Javier Ithurralde-Argerich
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Laura Rosner
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Mariana Rizzolo
- Department of Pathology, Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Alejandro Faerberg
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Rolando Puma
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Diego Ferro
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Camilo Duque
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Mirta Kujaruk
- Department of Pathology, Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Federico Cuenca-Abente
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
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17
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Danilova NV, Mikhailov IA, Oleynikova NA, Malkov PG. [E-cadherin expression in tumor emboli in gastric cancer]. Arkh Patol 2021; 83:11-19. [PMID: 34041891 DOI: 10.17116/patol20218303111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To determine the level of E-cadherin expression in tumor emboli, to compare it with expression in a tumor, to determine the dependence of E-cadherin expression in tumor emboli on the clinical and morphological characteristics of gastric cancer. MATERIAL AND METHODS We used samples of surgical material from 280 patients with a verified diagnosis of gastric cancer. E-cadherin expression was determined by immunohistochemical method. The results of the reactions were assessed semi-quantitatively and compared with the main clinical and morphological characteristics of gastric cancer (histological type according to the WHO classification 2019, histological type according to the classification of P. Lauren, clinical stage, depth of invasion (T), number of metastases in lymph nodes (N), presence or/absence of distant metastases (M), tumor localization in the stomach). RESULTS Among 280 cases of cancer, emboli were detected only in 67 cases, used for further analysis. The rest of the samples were excluded from the analysis, since emboli did not get into the sections during the cutting of immunohistochemical preparations. The expression of E-cadherin in tumor emboli was significantly higher (p<0.001) than in tumor tissue. At the same time, no cases identified where the level of E-cadherin decreased in emboli compared to the tumor. A significant increase in the expression of E-cadherin in tumor emboli compared to the primary tumor was noted for all histological types according to WHO 2019, for intermediate and diffuse types according to the P. Lauren classification (p<0.001). Comparison of expression in emboli and tumors for neoplasms with different depths of invasion (T), different stages and different localizations did not reveal statistically significant differences. An increase in the expression of E-cadherin in emboli compared to tumors was characterized by a higher level of significance in the presence of metastases (N1, N2, N3a, N3b; p<0.001) than in the absence of metastases (N0; p=0.016). CONCLUSION The study revealed a statistically significant increase in the expression of E-cadherin in tumor emboli compared to the primary tumor, which is evidence of its important role in maintaining the integrity of emboli and tumor dissemination.
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Affiliation(s)
- N V Danilova
- Lomonosov Moscow State University, Moscow, Russia
| | | | | | - P G Malkov
- Lomonosov Moscow State University, Moscow, Russia.,Russian Medical Academy for Continuous Professional Education, Moscow, Russia
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18
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Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer. Pharmaceuticals (Basel) 2021; 14:ph14050457. [PMID: 34066170 PMCID: PMC8151134 DOI: 10.3390/ph14050457] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.
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19
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Takeshima H, Niwa T, Yamashita S, Takamura-Enya T, Iida N, Wakabayashi M, Nanjo S, Abe M, Sugiyama T, Kim YJ, Ushijima T. TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest 2021; 130:5370-5379. [PMID: 32663196 DOI: 10.1172/jci124070] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 07/07/2020] [Indexed: 01/15/2023] Open
Abstract
Chronic inflammation is deeply involved in various human disorders, such as cancer, neurodegenerative disorders, and metabolic disorders. Induction of epigenetic alterations, especially aberrant DNA methylation, is one of the major mechanisms, but how it is induced is still unclear. Here, we found that expression of TET genes, methylation erasers, was downregulated in inflamed mouse and human tissues, and that this was caused by upregulation of TET-targeting miRNAs such as MIR20A, MIR26B, and MIR29C, likely due to activation of NF-κB signaling downstream of IL-1β and TNF-α. However, TET knockdown induced only mild aberrant methylation. Nitric oxide (NO), produced by NOS2, enhanced enzymatic activity of DNA methyltransferases (DNMTs), methylation writers, and NO exposure induced minimal aberrant methylation. In contrast, a combination of TET knockdown and NO exposure synergistically induced aberrant methylation, involving genomic regions not methylated by either alone. The results showed that a vicious combination of TET repression, due to NF-κB activation, and DNMT activation, due to NO production, is responsible for aberrant methylation induction in human tissues.
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Affiliation(s)
- Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tohru Niwa
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeji Takamura-Enya
- Department of Applied Chemistry, Kanagawa Institute of Technology, Kanagawa, Japan
| | - Naoko Iida
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Mika Wakabayashi
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Sohachi Nanjo
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Masanobu Abe
- Department of Oral and Maxillofacial Surgery, University of Tokyo Hospital, Tokyo, Japan.,Division for Health Service Promotion, University of Tokyo, Tokyo, Japan
| | - Toshiro Sugiyama
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
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20
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Casalino L, Verde P. Multifaceted Roles of DNA Methylation in Neoplastic Transformation, from Tumor Suppressors to EMT and Metastasis. Genes (Basel) 2020; 11:E922. [PMID: 32806509 PMCID: PMC7463745 DOI: 10.3390/genes11080922] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 07/30/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Among the major mechanisms involved in tumorigenesis, DNA methylation is an important epigenetic modification impacting both genomic stability and gene expression. Methylation of promoter-proximal CpG islands (CGIs) and transcriptional silencing of tumor suppressors represent the best characterized epigenetic changes in neoplastic cells. The global cancer-associated effects of DNA hypomethylation influence chromatin architecture and reactivation of repetitive elements. Moreover, recent analyses of cancer cell methylomes highlight the role of the DNA hypomethylation of super-enhancer regions critically controlling the expression of key oncogenic players. We will first summarize some basic aspects of DNA methylation in tumorigenesis, along with the role of dysregulated DNA methyltransferases and TET (Ten-Eleven Translocation)-family methylcytosine dioxygenases. We will then examine the potential contribution of epimutations to causality and heritability of cancer. By reviewing some representative genes subjected to hypermethylation-mediated silencing, we will survey their oncosuppressor functions and roles as biomarkers in various types of cancer. Epithelial-to-mesenchymal transition (EMT) and the gain of stem-like properties are critically involved in cancer cell dissemination, metastasis, and therapeutic resistance. However, the driver vs passenger roles of epigenetic changes, such as DNA methylation in EMT, are still poorly understood. Therefore, we will focus our attention on several aspects of DNA methylation in control of EMT and metastasis suppressors, including both protein-coding and noncoding genes.
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Affiliation(s)
- Laura Casalino
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80100 Naples, Italy
| | - Pasquale Verde
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80100 Naples, Italy
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21
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Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini PL, Fernández-Barrena MG, Avila MA. Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities. Int J Mol Sci 2020; 21:E5500. [PMID: 32752096 PMCID: PMC7432799 DOI: 10.3390/ijms21155500] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Pier-Luigi Lollini
- Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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22
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Wang SC, Yeu Y, Hammer STG, Xiao S, Zhu M, Hong C, Clemenceau JR, Yoon LY, Nassour I, Shen J, Agarwal D, Reznik SI, Mansour JC, Yopp AC, Zhu H, Hwang TH, Porembka MR. Hispanic/Latino Patients with Gastric Adenocarcinoma Have Distinct Molecular Profiles Including a High Rate of Germline CDH1 Variants. Cancer Res 2020; 80:2114-2124. [PMID: 32269045 PMCID: PMC7489496 DOI: 10.1158/0008-5472.can-19-2918] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/05/2020] [Accepted: 03/30/2020] [Indexed: 01/04/2023]
Abstract
Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes compared with patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients have been included in previous studies. To determine the genomic landscape of gastric cancer in Hispanic/Latino patients, we performed whole-exome sequencing (WES) and RNA sequencing on tumor samples from 57 patients; germline analysis was conducted on 83 patients. The results were compared with data from Asian and White patients published by The Cancer Genome Atlas. Hispanic/Latino patients had a significantly larger proportion of genomically stable subtype tumors compared with Asian and White patients (65% vs. 21% vs. 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type cancer, 7 (16%) had germline variants in CDH1. Variant carriers were significantly younger than noncarriers (41 vs. 50 years, P < 0.05). In silico algorithms predicted five variants to be deleterious. For two variants that were predicted to be benign, in vitro modeling demonstrated that these mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino patients with gastric cancer possess unique genomic landscapes, including a high rate of CDH1 germline variants that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary. SIGNIFICANCE: Gastric cancer in Hispanic/Latino patients has unique genomic profiles that may contribute to the aggressive clinical phenotypes seen in these patients.
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Affiliation(s)
- Sam C Wang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Yunku Yeu
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Suntrea T G Hammer
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Shu Xiao
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Min Zhu
- Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Changjin Hong
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jean R Clemenceau
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Lynn Y Yoon
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ibrahim Nassour
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeanne Shen
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Deepak Agarwal
- Department of Internal Medicine, University of Texas at Austin, Austin, Texas
| | - Scott I Reznik
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John C Mansour
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Adam C Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hao Zhu
- Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tae Hyun Hwang
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
| | - Matthew R Porembka
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
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23
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Corso G, Figueiredo J, De Angelis SP, Corso F, Girardi A, Pereira J, Seruca R, Bonanni B, Carneiro P, Pravettoni G, Guerini Rocco E, Veronesi P, Montagna G, Sacchini V, Gandini S. E-cadherin deregulation in breast cancer. J Cell Mol Med 2020; 24:5930-5936. [PMID: 32301282 PMCID: PMC7294130 DOI: 10.1111/jcmm.15140] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/31/2020] [Accepted: 02/06/2020] [Indexed: 12/13/2022] Open
Abstract
E‐cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E‐cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy.
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Affiliation(s)
- Giovanni Corso
- Division of Breast Surgery, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, Faculty of Medicine, University of Milan, Milan, Italy
| | - Joana Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | | | - Federica Corso
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Antonia Girardi
- Division of Breast Surgery, European Institute of Oncology IRCCS, Milan, Italy
| | - Joana Pereira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Raquel Seruca
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy
| | - Patricia Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Gabriella Pravettoni
- Department of Oncology and Hemato-Oncology, Faculty of Medicine, University of Milan, Milan, Italy.,Division of Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology IRCCS, Milan, Italy
| | - Elena Guerini Rocco
- Department of Oncology and Hemato-Oncology, Faculty of Medicine, University of Milan, Milan, Italy.,Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Paolo Veronesi
- Division of Breast Surgery, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, Faculty of Medicine, University of Milan, Milan, Italy
| | - Giacomo Montagna
- Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Virgilio Sacchini
- Department of Oncology and Hemato-Oncology, Faculty of Medicine, University of Milan, Milan, Italy.,Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sara Gandini
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
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24
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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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25
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Moridnia A, Tabatabaiefar MA, Zeinalian M, Minakari M, Kheirollahi M, Moghaddam NA. Novel Variants and Copy Number Variation in CDH1 Gene in Iranian Patients with Sporadic Diffuse Gastric Cancer. J Gastrointest Cancer 2020; 50:420-427. [PMID: 29577179 DOI: 10.1007/s12029-018-0082-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The aim of this study was to survey the nucleotide changes and copy number variations (CNV) in the CDH1 gene in Iranian patients with sporadic diffuse gastric cancer (SDGC). MATERIALS AND METHODS In this study, 28 patients were examined who upon gastrectomy had been diagnosed with SDGC according to the familial history and histopathological criteria which was confirmed by the pathologist. DNA extraction was performed from formalin-fixed paraffin-embedded tissues using a phenol-chloroform method following xylene deparaffinization. Determination of DNA sequence by Sanger was performed using PCR amplification of 16 exons and boundaries of intron/exon of CDH1 gene. Multiplex ligation-dependent probe amplification (MLPA) was performed on patients with pathogenic disorders in the sequence. RESULTS In total, patients included 20 males and 8 females. Of all patients, 12 patients were under 45 years old (early onset gastric cancer, EODC) and 16 patients were older. The tumor was diagnosed in the early TNM stage (I, II) in six patients and in late stages (III, IV) in 19 cases. Altogether, 16 variants (three exonic with one new variant and 13 intronic with nine new variants) were found in DNA sequencing of the CDH1 gene in five samples. Also, using MLPA, a new duplication in exon 9 and one deletion in exon 2 were detected in two other patients. Altogether, CDH1 variants were identified in seven out of 28 patients (25%). CONCLUSION Our study revealed several novel somatic variants in the CDH1 gene in Iranian patients with sporadic diffuse GC. Our data supports the hypothesis that mutations in CDH1 gene, and particularly the mutations we describe, should be considered, even in sporadic cases of gastric cancer. The presence of these mutations in patients raises important issues regarding genetic counseling and diagnostic test in DGC patients.
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Affiliation(s)
- Abbas Moridnia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mohammad Amin Tabatabaiefar
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mehrdad Zeinalian
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran
| | - Mohammad Minakari
- Internal medicine department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Majid Kheirollahi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable disease and Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, P.O.Box: 81746-73461, Isfahan, Iran.
| | - Noushin Afshar Moghaddam
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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26
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Novel role of Snail 1 in promoting tumor neoangiogenesis. Biosci Rep 2019; 39:BSR20182161. [PMID: 30975732 PMCID: PMC6509058 DOI: 10.1042/bsr20182161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 03/14/2019] [Accepted: 03/24/2019] [Indexed: 12/13/2022] Open
Abstract
Snail1 plays an important role in epithelial to mesenchymal transition (EMT) during tumor metastasis; however, whether Snai1 potentiates the process of neoangiogenesis is completely unknown. In the present study, tube formation assay was used to evaluate neoangiogenesis in vitro The expression of Snai1 and other pro-neoangiogenic factors was measured by quantitative real time PCR. Tumor derived endothelial cells (TDECs) were stimulated with fibroblast growth factor 1 (FGF1) or VEGF and formed more tubes compared with untreated, whereas cells treated with Sulforaphane had less tube formation. Silencing SNAI1 significantly attenuated tube formation accompanied by decreased CD31, CD34, and VWF expression in TDECs compared with control. In contrast, overexpression of Snai1 led to more CD31, CD34, and VWF expression and tube formation. To determine if the observed effects of SNAI1 on tube formation was a global phenomenon, the same assay was conducted in normal mesenchymal stem cells (MSCs). SNAI1 silencing did not have any effect on tube formation in MSCs. The expression of TIMP2, ENG, and HIF1A was up-regulated 3-fold or higher after silencing SNAI1, and ID1, VEGFA, PLG, LECT1, HPSE were shown down-regulated. Taken together, our study elucidates an important role of EMT inducer Snai1 in regulating tumor neoangiogenesis, suggesting a potential therapeutic target for overcoming tumor EMT.
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27
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Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/ HOPX/ Reprimo/ E-cadherin. Oncotarget 2019; 10:2423-2434. [PMID: 31069006 PMCID: PMC6497431 DOI: 10.18632/oncotarget.26814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 01/19/2019] [Indexed: 12/12/2022] Open
Abstract
Background Early detection of remnant gastric cancer (RGC) is required to reduce the risk of death, but long-term endoscopic surveillance is difficult after gastrectomy. In this study, data for the methylation status of 4 methylation genes (CDO1, HOPX, Reprimo, and E-cadherin) to predict the onset of RGC are presented. Results The 4 genes showed hypermethylation in RGC tumors in contrast to the corresponding non-cancerous mucosa tissues. The methylation level in the non-cancerous mucosa tissues of the initial surgery was obviously high in initial malignant disease for CDO1 (P = 0.0001), while in initial benign one for E-cadherin (P = 0.003). Promoter DNA methylation status in the remnant non-cancerous mucosa tissues together with the basic clinical data in turn predicted either initial malignant disease or initial benign disease with a high AUC score of 0.94, suggesting that methylation events are differentially recognized between the initial malignant and benign disease. We then finally confirmed that 4 genes hypermethylation of the non-cancerous tissues by biopsy prior to onset of RGC could predict terms until RGC occurred (P < 0.0001). Methods A total of 58 RGC patients were used to establish the model. The 4 genes promoter methylation were analyzed for DNA obtained from the patient's specimens using quantitative methylation specific polymerase chain reaction. Conclusions This risk model would help provide guidance for endoscopic surveillance plan of RGC after gastrectomy.
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28
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Korivi BR, Faria S, Aly A, Sun J, Patnana M, Jensen CT, Wagner-Bartak N, Bhosale PR. Intestinal and diffuse gastric cancer: a retrospective study comparing primary sites. Clin Imaging 2019; 56:33-40. [PMID: 30870726 DOI: 10.1016/j.clinimag.2019.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 02/12/2019] [Accepted: 03/01/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE We assessed differences in primary sites and spread patterns of the intestinal and diffuse subtypes of gastric carcinoma. We also compared survival outcomes based on spread patterns. MATERIALS AND METHODS For this retrospective IRB-approved study, our institutional imaging database was mined for patients with gastric cancer. We included 99 treatment-naïve patients. Patient demographics, pathologic data, tumor classification, primary tumor site, and metastasis sites were recorded. Pearson's chi-squared test was used to correlate tumor pathology with metastatic sites. Kaplan-Meier survival curves were compared between baseline metastatic types. A heat map was created based on the relative frequencies of metastatic sites for each primary tumor site. RESULTS Of the 99 patients, 66 patients had intestinal and 33 had diffuse gastric carcinoma. The intestinal subtype was significantly associated with hepatic metastases (p < 0.001). Diffuse subtype was associated with peritoneal metastases, including omental metastases (p < 0.006), gastrosplenic ligament involvement (p < 0.004), and mesocolonic implants (p < 0.008). Patients with primary gastric tumors occurring at the greater curvature had longer overall survival than those with primary sites at the antrum, GE junction and lesser curvature (p = 0.0015). Patients with peritoneal metastases had a significantly shorter overall survival than patients without peritoneal metastases (p < 0.001). Patients without mesocolon, gastrohepatic ligament, and gastrosplenic ligament involvement had a better survival (p = 0.005, p = 0.0002, and p = 0.0005, respectively). Presence of hepatic metastases had no effect on survival (p = 0.16). CONCLUSION Recognizing distinctive spread patterns for intestinal versus diffuse gastric carcinoma can aid radiologists in diagnosis and guide clinical management.
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Affiliation(s)
- Brinda Rao Korivi
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
| | - Silvana Faria
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
| | - Asran Aly
- National Cancer Institute, Cairo University, Egypt
| | - Jia Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1411, Houston, TX 77030, United States of America.
| | - Madhavi Patnana
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
| | - Corey T Jensen
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
| | - Nicolaus Wagner-Bartak
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
| | - Priya R Bhosale
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1473, Houston, TX 77030, United States of America.
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29
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Bustos-Carpinteyro AR, Oliveira C, Sousa A, Oliveira P, Pinheiro H, Carvalho J, Magaña-Torres MT, Flores-Miramontes MG, Aguilar-Lemarroy A, Jave-Suárez LF, Peregrina-Sandoval J, Cruz-Ramos JA, Sánchez-López JY. CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer. BMC Cancer 2019; 19:69. [PMID: 30642281 PMCID: PMC6332846 DOI: 10.1186/s12885-019-5294-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 01/07/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. METHODS We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. RESULTS Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. CONCLUSIONS While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.
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Affiliation(s)
- Andrea Rebeca Bustos-Carpinteyro
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México.,Doctorado en Genética Humana, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Carla Oliveira
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal.,Faculty of Medicine, University of Porto, Porto, Portugal
| | - Abel Sousa
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - Patricia Oliveira
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - Hugo Pinheiro
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal.,Department of Internal Medicine, Centro Hospitalar Tâmega e Sousa Avenida do Hospital Padre Américo, N° 210 4564-007, Guilhufe - Penafiel, Portugal
| | - Joana Carvalho
- Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S; University of Porto, Porto, Portugal
| | - María Teresa Magaña-Torres
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México
| | - María Guadalupe Flores-Miramontes
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Adriana Aguilar-Lemarroy
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Luis Felipe Jave-Suárez
- División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México
| | - Jorge Peregrina-Sandoval
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular. Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, CP 45510, Nextipac, Jalisco, México
| | | | - Josefina Yoaly Sánchez-López
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada N. 800, Col. Independencia, C. P. 44340, Guadalajara, Jalisco, México.
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30
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Cho SJ, Yoon C, Lee JH, Chang KK, Lin JX, Kim YH, Kook MC, Aksoy BA, Park DJ, Ashktorab H, Smoot DT, Schultz N, Yoon SS. RETRACTED: KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition. Clin Cancer Res 2018; 24:6556-6569. [PMID: 30108106 PMCID: PMC6295255 DOI: 10.1158/1078-0432.ccr-17-1679] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/13/2017] [Accepted: 08/09/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C (KMT2C) as a frequently mutated gene and examined its role in DGA progression. EXPERIMENTAL DESIGN We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C (KMT2C) was analyzed in DGA cell lines and in patient tumors. RESULTS KMT2C was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage (P = 0.023) and worse overall survival (P = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. CONCLUSIONS KMT2C is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.
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Affiliation(s)
- Soo-Jeong Cho
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
- Center for Gastric Cancer, National Cancer Center, Goyang, South Korea
| | - Changhwan Yoon
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Jun Ho Lee
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Kevin K Chang
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Jian-Xian Lin
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Young-Ho Kim
- Division of Clinical Research, Rare Cancer Branch, National Cancer Center, Goyang, South Korea
| | - Myeong-Cherl Kook
- Center for Gastric Cancer, National Cancer Center, Goyang, South Korea
| | - Bülent Arman Aksoy
- Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Do Joong Park
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | | | - Duane T Smoot
- Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee
| | - Nikolaus Schultz
- Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Sam S Yoon
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
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Early Hereditary Diffuse Gastric Cancer (eHDGC) is Characterized by Subtle Genomic Instability and Active DNA Damage Response. Pathol Oncol Res 2018; 25:711-721. [PMID: 30547291 DOI: 10.1007/s12253-018-0547-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 11/16/2018] [Indexed: 12/26/2022]
Abstract
Diffuse gastric cancer (DGC) is one of the two primary types of stomach cancer. Carriers of germline mutations in the gene encoding E-cadherin are predisposed to DGC. The primary aim of the present study was to determine if genomic instability is an early event in DGC and how it may lead to disease progression. Chromosomal aberrations in early intramucosal hereditary diffuse gastric cancer (eHDGC) were assessed using array comparative genomic hybridization (array CGH). Notably, no aneuploidy or other large-scale chromosomal rearrangements were detected. Instead, all aberrations affected small regions (< 4.8 Mb) and were predominantly deletions. Analysis of DNA sequence patterns revealed that essentially all aberrations possessed the characteristics of common fragile sites. These results and the results of subsequent immunohistochemical examinations demonstrated that unlike advanced DGC, eHDGCs is characterized by low levels of genomic instability at fragile sites. Furthermore, they express an active DNA damage response, providing a molecular basis for the observed indolence of eHDGC. This finding is an important step to understanding the pathology underlying natural history of DGC and supports a revision of the current definition of eHDGC as a malignant disease.
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Mohsenzadeh M, Sadeghi RN, Vahedi M, Kamani F, Hashemi M, Asadzadeh H, Zali MR. Promoter hypermethylation of RAR-β tumor suppressor gene in gastric carcinoma: Association with histological type and clinical outcomes. Cancer Biomark 2018; 20:7-15. [PMID: 28759951 DOI: 10.3233/cbm-160331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND While gastric cancer is a common cancer in the world and Iran, its molecular mechanisms are not fully understood as yet. Epigenetic modifications can lead to alteration of gene expression and development of tumorigenesis mechanisms. METHODS To clarify the difference in DNA methylation pattern of histological types in gastric carcinoma, CpG islands in the promoters of retinoic acid receptor β gene (RAR-β) was studied using methylation-specific PCR. RESULTS In gastric cancer tissues, hypermethylation frequency of RAR-β gene was respectively 61 and 33% for diffuse and intestinal type. In diffuse type, hypermethylation of RAR-β has been significantly associated with invasion (P= 0.007), differentiation (P= 0.033) and location (P= 0.012) of the tumor. However, hypermethylation of RAR-β correlated only with tumor size (P= 0.029) in intestinal type. For adjacent non-tumor samples, hypermethylation of RAR-β was not detected and there was no significant association between age of diagnosis and hypermethylation of RAR-β in both types of gastric cancer. CONCLUSIONS These results support previous findings denoting a distinct profile of promoter hypermethylation status in the development of the intestinal and diffuse type of gastric carcinoma and the process of the tumorigenesis in these subtypes of gastric cancer is different from each other.
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Affiliation(s)
- Maedeh Mohsenzadeh
- Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Rouhallah Najjar Sadeghi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Faculty of Medicine, Department of Clinical Biochemistry, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohsen Vahedi
- Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Fereshteh Kamani
- Department of Surgery, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Hamid Asadzadeh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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Yoshii T, Miyagi Y, Nakamura Y, Kobayashi O, Kameda Y, Ohkawa S. Pilot Research for the Correlation between the Expression Pattern of E-cadherin-β-Catenin Complex and Lymph Node Metastasis in Early Gastric Cancer. TUMORI JOURNAL 2018; 99:234-8. [DOI: 10.1177/030089161309900219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Aims and background Early gastric cancer without lymph node metastasis can be treated with minimally invasive endoscopic surgery. Hence, a better modality for predicting lymph node metastasis should be beneficial to early gastric cancer patients who may only require minimally invasive treatment. In vitro, phosphorylation of β-catenin induces the loss of membranous β-catenin and E-cadherin, subsequently increasing the potential for metastasis. We investigated the behavior of these molecules comparing lymph node metastasis-positive and lymph node metastasis-negative groups, using the specimens from the patients with early gastric cancer. This was a pilot research evaluating the usefulness of combined analysis of these molecules in predicting lymph node metastasis in early gastric cancer. Methods The clinicopathological features and immunohistochemical expression patterns of E-cadherin and β-catenin in the primary lesion were studied retrospectively in 28 patients (lymph node metastasis-positive versus lymph node metastasis-negative: 14 vs 14) selected from 272 patients. These patients underwent radical surgery for the early gastric cancer treatment from April 2000 to March 2004 at our hospital. All patients gave written informed consent to use their tissues for the clinical study. Statistical analyses were performed by the chi-square test and Mann-Whitney test. Results More loss of membranous E-cadherin was observed in the lymph node metastasis-positive group than in the lymph node metastasis-negative group. Although the finding was slightly more marked in the intestinal than in the diffuse type early gastric cancer, there was no statistical significance. Loss of membranous β-catenin showed a similar trend and no statistical significance. When we evaluated the expression patterns of both molecules, dual loss of membranous E-cadherin and β-catenin significantly correlated with lymph node metastasis [dual loss in lymph node metastasis-positive versus lymph node metastasis-negative patients: 12 (86%) vs 6 (43%), P = 0.046]. Additionally, corresponding proportions in intestinal type early gastric cancer were 5 of 6 (83%) vs 0 of 6 (0%), P = 0.015. Conclusions Based on our results, the combined analysis of E-cadherin and β-catenin localizations may be helpful to accurately predict lymph node metastasis in intestinal type early gastric cancer.
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Affiliation(s)
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Yokohama, Japan
| | | | | | - Yoichi Kameda
- Division of Pathology, Kanagawa Cancer Center, Yokohama, Japan
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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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36
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Total Gastrectomy for Hereditary Diffuse Gastric Cancer at a Single Center: Postsurgical Outcomes in 41 Patients. Ann Surg 2017; 266:1006-1012. [PMID: 27759617 DOI: 10.1097/sla.0000000000002030] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC). BACKGROUND HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy. METHODS A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected. RESULTS Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be "as expected" by 40% of patients and "better than expected" by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy. CONCLUSION Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.
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37
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Menbari MN, Nasseri S, Menbari N, Mehdiabadi R, Alipur Y, Roshani D. The -160 (C>A) CDH1 Gene Promoter Polymorphism and Its Relationship with Survival of Patients with Gastric Cancer in
Kurdistan. Asian Pac J Cancer Prev 2017; 18:1561-1565. [PMID: 28669168 PMCID: PMC6373814 DOI: 10.22034/apjcp.2017.18.6.1561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Introduction: Gastric cancer (GC) is the fourth most common type of neoplasm and the second cause of malignancy-related death across much of the world. Complex multi-factorial processes are involved in its genesis, classified in two determinant clusters: non-genetic and genetic. Variation in CDH1 gene expression may play an important role in increasing risk of diffuse and intestinal subtypes of GC. This tumor suppressor gene, located on chromosome 16q22.1, encodes a trans membrane glycoprotein called epithelial cadherin (E-cadherin). Materials and Methods: In this historical cohort study, from June 2004 to Journey 2005 we collected 50 samples from Kurdish patients with stage II pathologically diagnosed gastric cancer that underwent surgery. Tumor tissues were paraffin-embedded along with 54 control samples from non-ulcer dyspepsia (NUD) cases undergoing upper gastrointestinal endoscopy. Three biopsies were captured by endoscopy from each individual’s gastric antrum. Result: The mean age of the patients was 59.5±2 years. Some 23 cases (53.4%) had the CC genotype, 19 AC and 1 AA. H.pylori infection was noted in 30 patients (69%). Survival rates of gastric cancer patients were 90.7% in the first year, 39.5% in the second year and 6.9% in the third year. Female patients had higher survival rates (P=0.004). Conclusion: In this study we found that frequencies of -160(C>A) CDH1 genotypes were not comparable in H.pylori-infected and H.pylori-uninfected subjects in both case and control groups. These findings suggest that -160 (C>A) CDH1 polymorphism is not related with H.pylori infection susceptibility. In addition we found no significant relationship between the CDH1 -160(C/A) promoter polymorphism with predisposition to gastric cancer.
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Affiliation(s)
- Mohammad Nazir Menbari
- Cellular and Molecular Research Center, Kurdistan University of Medical
Sciences, Sanandaj, Iran.
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38
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Alvizi L, Ke X, Brito LA, Seselgyte R, Moore GE, Stanier P, Passos-Bueno MR. Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects. Sci Rep 2017; 7:2441. [PMID: 28550290 PMCID: PMC5446392 DOI: 10.1038/s41598-017-02721-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 04/18/2017] [Indexed: 01/09/2023] Open
Abstract
Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP. MVPs were enriched in regulatory and active regions of the genome and in pathways already implicated in craniofacial development. In an independent UK cohort (171 NSCLP, 177 controls), we replicated 4 out of 11 tested MVPs. We demonstrated a significant positive correlation between blood and lip tissue DNA methylation, indicating blood as a suitable tissue for NSCLP methylation studies. Next, we quantified CDH1 promoter methylation levels in CDH1 mutation-positive families, including penetrants, non-penetrants or non-carriers for NSCLP. We found methylation levels to be significantly higher in the penetrant individuals. Taken together, our results demonstrated the association of methylation at specific genomic locations as contributing factors to both non-familial and familial NSCLP and altered DNA methylation may be a second hit contributing to penetrance.
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Affiliation(s)
- Lucas Alvizi
- Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
| | - Xiayi Ke
- Genetics and Genomic Medicine, Institute of Child Health, University College of London, London, UK
| | - Luciano Abreu Brito
- Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
| | - Rimante Seselgyte
- Genetics and Genomic Medicine, Institute of Child Health, University College of London, London, UK
| | - Gudrun E Moore
- Genetics and Genomic Medicine, Institute of Child Health, University College of London, London, UK
| | - Philip Stanier
- Genetics and Genomic Medicine, Institute of Child Health, University College of London, London, UK.
| | - Maria Rita Passos-Bueno
- Centro de Pesquisas Sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
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Gan WJ, Wang JR, Zhu XL, He XS, Guo PD, Zhang S, Li XM, Li JM, Wu H. RARγ-induced E-cadherin downregulation promotes hepatocellular carcinoma invasion and metastasis. J Exp Clin Cancer Res 2016; 35:164. [PMID: 27756432 PMCID: PMC5069892 DOI: 10.1186/s13046-016-0441-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/08/2016] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Aberrant expression of Retinoic acid receptor γ (RARγ) is implicated in cancer development. Our previous study identified that RARγ functions as a tumor promoter to drive hepatocellular carcinoma (HCC) growth. However, its contribution to HCC invasion and metastasis remains unclear. METHODS RARγ expression in clinical HCC samples was detected by western blot and immunohistochemistry. The relationship between RARγ expression levels and the clinical characteristics were evaluated. HCC cell line MHCC-97H were stably knocked down RARγ using a lentivirus vector-based shRNA technique. The cells were analyzed by migration and invasion assays, and injected into nude mice to assess tumor metastasis. E-cadherin expression regulated by RARγ was examined by qPCR, western blot and immunofluorescence staining. RESULTS The expression of RARγ is significantly upregulated in human HCC tissues. Moreover, its expression positively correlates with tumor size, distant metastasis and TNM stage, and negatively correlates with length of survival of HCC patients. Knockdown of RARγ markedly inhibits HCC cell invasion and metastasis both in vitro and in vivo. Mechanistic investigations reveal that RARγ functions through regulation of NF-κB-mediated E-cadherin downregulation to promote HCC invasion and metastasis. Notably, RARγ expression status negatively correlates with E-cadherin expression in HCC cell lines and clinical HCC samples. CONCLUSIONS These findings demonstrate that RARγ could promote HCC invasion and metastasis by regulating E-cadherin reduction, and implicate new strategies to aggressively treat HCC through targeting RARγ/E-cadherin signaling axis.
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Affiliation(s)
- Wen-Juan Gan
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
- The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Jing-Ru Wang
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
| | - Xiao-Li Zhu
- The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Xiao-Shun He
- The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Peng-Da Guo
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
| | - Shen Zhang
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
| | - Xiu-Ming Li
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
| | - Jian-Ming Li
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
| | - Hua Wu
- Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123 China
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40
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Maiuri AR, O'Hagan HM. Interplay Between Inflammation and Epigenetic Changes in Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:69-117. [PMID: 27865469 DOI: 10.1016/bs.pmbts.2016.09.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immune responses can suppress tumorigenesis, but also contribute to cancer initiation and progression suggesting a complex interaction between the immune system and cancer. Epigenetic alterations, which are heritable changes in gene expression without changes to the DNA sequence, also play a role in carcinogenesis through silencing expression of tumor suppressor genes and activating oncogenic signaling. Interestingly, epithelial cells at sites of chronic inflammation undergo DNA methylation alterations that are similar to those present in cancer cells, suggesting that inflammation may initiate cancer-specific epigenetic changes in epithelial cells. Furthermore, epigenetic changes occur during immune cell differentiation and participate in regulating the immune response, including the regulation of inflammatory cytokines. Cancer cells utilize epigenetic silencing of immune-related genes to evade the immune response. This chapter will detail the interactions between inflammation and epigenetics in tumor initiation, promotion, and immune evasion and how these connections are being leveraged in cancer prevention and treatment.
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Affiliation(s)
- A R Maiuri
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States
| | - H M O'Hagan
- Medical Sciences, Indiana University School of Medicine, Bloomington, IN, United States; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States.
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Ahmad SA, Xia BT, Bailey CE, Abbott DE, Helmink BA, Daly MC, Thota R, Schlegal C, Winer LK, Ahmad SA, Al Humaidi AH, Parikh AA. An update on gastric cancer. Curr Probl Surg 2016; 53:449-90. [PMID: 27671911 DOI: 10.1067/j.cpsurg.2016.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 08/03/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Syed A Ahmad
- Division of Surgical Oncology, University of Cincinnati Cancer Institute, University of Cincinnati College of Medicine, Cincinnati, OH.
| | - Brent T Xia
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Christina E Bailey
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Daniel E Abbott
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Beth A Helmink
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Meghan C Daly
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Ramya Thota
- Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
| | - Cameron Schlegal
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Leah K Winer
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | | | - Ali H Al Humaidi
- Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH
| | - Alexander A Parikh
- Division of Hepatobiliary, Pancreas and Gastrointestinal Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN
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Higuchi K, Inokuchi M, Takagi Y, Ishikawa T, Otsuki S, Uetake H, Kojima K, Kawano T. Cadherin 5 expression correlates with poor survival in human gastric cancer. J Clin Pathol 2016; 70:217-221. [PMID: 27466381 DOI: 10.1136/jclinpath-2016-203640] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 06/29/2016] [Accepted: 07/02/2016] [Indexed: 02/06/2023]
Abstract
AIMS Although expressed in tumour cells of various malignancies, cadherin 5 (CDH5), also known as vascular endothelial cadherin, plays an important role in homotypic cell-cell adhesion among epithelial cells. However, the clinical significance of CDH5 expression in gastric cancer has not been sufficiently demonstrated. In this study, CDH5 expression in gastric cancer was evaluated and the correlations between CDH5 expression and the clinicopathological features and outcomes of the disease were examined. METHODS Differentiated-type gastric adenocarcinomas obtained from 102 patients who underwent gastrectomy were analysed. CDH5 expression was assessed by immunohistochemical staining of the membranes of the cancer cells. RESULTS High CDH5 expression was significantly associated with the following clinicopathological variables related to tumour progression: depth of invasion (p=0.012), venous invasion (p=0.013), lymphatic invasion (p=0.001), metastatic lymph nodes (p=0.009), pathological stage (p=0.008) and distant metastasis or recurrent disease (p=0.009). Patients with high CDH5 expression had significantly poorer disease-specific survival (p=0.021), although CDH5 was not determined to be an independent prognostic factor by multivariate analysis. CONCLUSIONS CDH5 may play a key role in the progression or metastasis of differentiated-type gastric cancer and serve as a target for its treatment.
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Affiliation(s)
- Kyoko Higuchi
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mikito Inokuchi
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoko Takagi
- Department of Surgical Specialties, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiaki Ishikawa
- Department of Surgical Specialties, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sho Otsuki
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Uetake
- Department of Surgical Specialties, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyuki Kojima
- Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuyuki Kawano
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
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43
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MA JUNLI, SHEN HONG, KAPESA LINDA, ZENG SHAN. Lauren classification and individualized chemotherapy in gastric cancer. Oncol Lett 2016; 11:2959-2964. [PMID: 27123046 PMCID: PMC4840723 DOI: 10.3892/ol.2016.4337] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 02/05/2016] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of the most common malignancies worldwide. During the last 50 years, the histological classification of gastric carcinoma has been largely based on Lauren's criteria, in which gastric cancer is classified into two major histological subtypes, namely intestinal type and diffuse type adenocarcinoma. This classification was introduced in 1965, and remains currently widely accepted and employed, since it constitutes a simple and robust classification approach. The two histological subtypes of gastric cancer proposed by the Lauren classification exhibit a number of distinct clinical and molecular characteristics, including histogenesis, cell differentiation, epidemiology, etiology, carcinogenesis, biological behaviors and prognosis. Gastric cancer exhibits varied sensitivity to chemotherapy drugs and significant heterogeneity; therefore, the disease may be a target for individualized therapy. The Lauren classification may provide the basis for individualized treatment for advanced gastric cancer, which is increasingly gaining attention in the scientific field. However, few studies have investigated individualized treatment that is guided by pathological classification. The aim of the current review is to analyze the two major histological subtypes of gastric cancer, as proposed by the Lauren classification, and to discuss the implications of this for personalized chemotherapy.
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Affiliation(s)
- JUNLI MA
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
- Key Laboratory for Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - HONG SHEN
- Key Laboratory for Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - LINDA KAPESA
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - SHAN ZENG
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
- Key Laboratory for Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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44
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Eftang LL, Klajic J, Kristensen VN, Tost J, Esbensen QY, Blom GP, Bukholm IRK, Bukholm G. GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer. BMC Cancer 2016; 16:225. [PMID: 26984265 PMCID: PMC4794813 DOI: 10.1186/s12885-016-2247-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 03/02/2016] [Indexed: 12/31/2022] Open
Abstract
Background A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Methods Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Results Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. Conclusions The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2247-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lars Lohne Eftang
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway. .,Department of Gastrointestinal Surgery, Akershus University Hospital, N-1478, Nordbyhagen, Lørenskog, Norway.
| | - Jovana Klajic
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Vessela N Kristensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway.,Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet Montebello, Oslo, Norway
| | - Jörg Tost
- Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA - Institut de Génomique, Evry, France
| | - Qin Ying Esbensen
- Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University Hospital, Division of Medicine, Lørenskog, Norway
| | - Gustav Peter Blom
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | - Ida Rashida Khan Bukholm
- Institute of Clinical Medicine, Akershus University Hospital and University of Oslo, Lørenskog, Norway
| | - Geir Bukholm
- Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.,Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
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Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A, Taieb J. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol 2015; 21:11428-11438. [PMID: 26523107 PMCID: PMC4616218 DOI: 10.3748/wjg.v21.i40.11428] [Citation(s) in RCA: 217] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/14/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
While the incidence of gastric cancer has decreased worldwide in recent decades, the incidence of signet-ring cell carcinoma (SRCC) is rising. SRCC has a specific epidemiology and oncogenesis and has two forms: early gastric cancer, which can be resected endoscopically in some cases and which has a better outcome than non-SRCC, and advanced gastric cancer, which is generally thought to have a worse prognosis and lower chemosensitivity than non-SRCC. However, the prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage. It therefore remains unclear if a specific therapeutic strategy is justified, as the benefit of perioperative chemotherapy and the value of taxane-based chemotherapy are unclear. In this review we analyze recent data on the epidemiology, oncogenesis, prognosis and specific therapeutic strategies in both early and advanced SRCC of the stomach and in hereditary diffuse gastric cancer.
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46
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The role of Snail1 transcription factor in colorectal cancer progression and metastasis. Contemp Oncol (Pozn) 2015; 19:265-70. [PMID: 26557772 PMCID: PMC4631295 DOI: 10.5114/wo.2014.42173] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 12/05/2013] [Accepted: 02/03/2014] [Indexed: 01/21/2023] Open
Abstract
Snail1 is a zinc-finger transcription factor, which plays a role in colorectal cancer development by silencing E-cadherin expression and inducing epithelialmesenchymal transition (EMT). During EMT tumour cells acquire a mesenchymal phenotype that is responsible for their invasive activities. Consequently, Snail1 expression in colorectal cancer is usually associated with progression and metastasis. Some studies revealed that about 77% of colon cancer samples display Snail1 immunoreactivity both in activated fibroblasts and in carcinoma cells that have undergone EMT. Therefore, expression of this factor in the stroma may indicate how many cells possess the abilities to escape from the primary tumour mass, invade the basal lamina and colonise distant target organs. Blocking snail proteins activity has the potential to avert cancer cell metastasis by interfering with such cellular processes as remodelling of the actin cytoskeleton, migration and invasion, which are clearly associated with the aggressive phenotype of the disease. Moreover, the link between factors from the snail family and cancer stem cells suggests that inhibitory agents may also prove their potency as inhibitors of cancer recurrence.
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47
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Yu Q, Guo Q, Chen L, Liu S. Clinicopathological significance and potential drug targeting of CDH1 in lung cancer: a meta-analysis and literature review. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2171-8. [PMID: 25931811 PMCID: PMC4404966 DOI: 10.2147/dddt.s78537] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background CDH1 is a protein encoded by the CDH1 gene in humans. Mutations in this gene are linked with several types of cancer. Loss of CDH1 function contributes to the progression of cancer by increasing proliferation, invasion, and/or metastasis. However, the association between and clinicopathological significance of CDH1 promoter methylation and lung cancer remains unclear. In this study, we systematically reviewed the studies of CDH1 promoter methylation and lung cancer, and evaluated the association between CDH1 promoter methylation and lung cancer using meta-analysis methods. Methods A comprehensive search of the PubMed and Embase databases was performed up to July 2014. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. Results Finally, an analysis of 866 patients with non-small cell lung cancer from 13 eligible studies was performed. The CDH1 methylation level in the cancer group was significantly higher than in the controls (OR 3.89, 95% confidence interval [CI] 2.87–5.27, P<0.00001). However, there were no correlations between CDH1 promoter methylation and clinicopathological characteristics (sex status, OR 0.78, 95% CI 0.41–1.50, P=0.46; smoking history, OR 0.97, 95% CI 0.53–1.79, P=0.93; pathological type, OR 0.97, 95% CI 0.59–1.60, P=0.91; clinical staging, OR 1.48, 95% CI 0.81–2.68, P=0.2; lymph node metastasis, OR 0.68, 95% CI 0.13–3.63, P=0.65; or differentiation degree, OR 1.01, 95% CI 0.34–3.02, P=0.99). Conclusion The results of this meta-analysis suggest that CDH1 methylation is associated with an increased risk of lung cancer. CDH1 hypermethylation, which induces inactivation of the CDH1 gene, plays an important role in carcinogenesis and may serve as a potential drug target in lung cancer. However, CDH1 methylation does not correlate with other factors, such as smoking history, clinical stage, pathological type, sex status, lymph node metastasis, or degree of differentiation.
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Affiliation(s)
- Qiaowen Yu
- Shandong Provincial Key Laboratory of Mental Disorders, Research Center for Sectional and Imaging Anatomy, Shandong University School of Medicine, Beijing, People's Republic of China
| | - Qisen Guo
- Respiratory Medicine, Shandong Cancer Hospital, Jinan, Beijing, People's Republic of China
| | - Liangan Chen
- Department of Respiratory Diseases, People's Liberation Army General Hospital, Beijing, People's Republic of China
| | - Shuwei Liu
- Shandong Provincial Key Laboratory of Mental Disorders, Research Center for Sectional and Imaging Anatomy, Shandong University School of Medicine, Beijing, People's Republic of China
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48
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Zeng W, Zhu J, Shan L, Han Z, Aerxiding P, Quhai A, Zeng F, Wang Z, Li H. The clinicopathological significance of CDH1 in gastric cancer: a meta-analysis and systematic review. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2149-57. [PMID: 25926721 PMCID: PMC4403748 DOI: 10.2147/dddt.s75429] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Background CDH1 is a protein encoded by the CDH1 gene in humans. Loss of CDH1 function contributes to cancer progression by increasing proliferation, invasion, and/or metastasis. However, the association and clinicopathological significance between CDH1 hypermethylation and gastric cancer (GC) remains unclear. In this study, we systematically reviewed the studies of CDH1 hypermethylation and GC, and evaluated the association between CDH1 hypermethylation and GC using meta-analysis methods. Methods A comprehensive search of the PubMed and Embase databases was performed for publications up to July 2014. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. Results A final analysis of 1,079 GC patients from 14 eligible studies was performed. CDH1 hypermethylation level in the cancer group was significantly higher compared to the normal gastric mucosa (OR =8.55, 95% confidence interval [CI]: 2.39–33.51, Z=5.47, P<0.00001). CDH1 hypermethylation was not significantly higher in GC than in adjacent gastric mucosa (OR =3.68, 95% CI: 0.96–14.18, Z=1.90, P=0.06). However, CDH1 hypermethylation was higher in adjacent gastric mucosa compared to that in normal gastric mucosa (OR =2.55, 95% CI: 1.22–5.32, Z=2.49, P<0.01). In addition, CDH1 hypermethylation was correlated with Helicobacter pylori (HP) status in GC. The pooled OR from six studies including 280 HP-positive GCs and 193 HP-negative GCs is 1.72 (95% CI: 1.13–2.61, Z=2.55, P=0.01). Conclusion The results of this meta-analysis reveal that CDH1 hypermethylation levels in cancer and adjacent gastric mucosa are significantly higher compared to normal gastric mucosa. Thus, CDH1 hypermethylation is significantly correlated with GC risk. CDH1 hypermethylation is correlated with HP status, indicating that it plays a more important role in the pathogenesis of HP-positive GC and might be an interesting potential drug target for GC patients.
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Affiliation(s)
- Wei Zeng
- College of Public Health, Xinjiang Medical University, Xinjiang, People's Republic of China ; First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Jinfeng Zhu
- Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Li Shan
- First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Zhigang Han
- First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Patiguli Aerxiding
- First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Amina Quhai
- First Department of Lung Cancer Chemotherapy, The Affiliated Cancer Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Fanye Zeng
- Department of Oncology, Traditional Chinese Medical Hospital Affiliated to Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Ziwei Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Huiwu Li
- School of Basic Medicine, Xinjiang Medical University, Xinjiang, People's Republic of China
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Zhao Y, Feng F, Zhou YN. Stem cells in gastric cancer. World J Gastroenterol 2015; 21:112-123. [PMID: 25574084 PMCID: PMC4284326 DOI: 10.3748/wjg.v21.i1.112] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 09/19/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Cancer stem cells (CSCs), which were first identified in acute myeloid leukemia and subsequently in a large array of solid tumors, play important roles in cancer initiation, dissemination and recurrence. CSCs are often transformed tissue-specific stem cells or de-differentiated transit amplifying progenitor cells. Several populations of multipotent gastric stem cells (GSCs) that reside in the stomach have been determined to regulate physiological tissue renewal and injury repair. These populations include the Villin+ and Lgr5+ GSCs in the antrum, the Troy+ chief cells in the corpus, and the Sox2+ GSCs that are found in both the antrum and the corpus. The disruption of tumor suppressors in Villin+ or Lgr5+ GSCs leads to GC in mouse models. In addition to residing GSCs, bone marrow-derived cells can initiate GC in a mouse model of chronic Helicobacter infection. Furthermore, expression of the cell surface markers CD133 or CD44 defines gastric CSCs in mouse models and in human primary GC tissues and cell lines. Targeted elimination of CSCs effectively reduces tumor size and grade in mouse models. In summary, the recent identification of normal GSCs and gastric CSCs has greatly improved our understanding of the molecular and cellular etiology of GC and will aid in the development of effective therapies to treat patients.
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50
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Ketner EP, Chu QD, Karpeh MS, Khushalani NI. Gastric Cancer. Surg Oncol 2015. [DOI: 10.1007/978-1-4939-1423-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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