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Jiang Q, Geng P, Zhang Y, Yang M, Zhu J, Zhang M, Wang Y, Feng Y, Sun X. Associations between CDH1 gene polymorphisms and the risk of gastric cancer: A meta-analysis based on 44 studies. Medicine (Baltimore) 2024; 103:e38244. [PMID: 38847676 PMCID: PMC11155553 DOI: 10.1097/md.0000000000038244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/25/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND Numerous studies have investigated the association between CDH1 polymorphisms and gastric cancer (GC) risk. However, the results have been inconsistent and controversial. To further determine whether CDH1 polymorphisms increase the risk of GC, we conducted a meta-analysis by pooling the data. METHODS Relevant case-control studies were collected from PubMed, Embase, Web of Science and Cochrane databases up to January 7, 2024. Subsequently, odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of correlations. A sensitivity analysis was performed to evaluate the robustness and reliability of these included studies. RESULTS A total of 25 articles including 44 studies, were included in this meta-analysis, including 26 studies on rs16260, 6 studies on rs3743674, 7 studies on rs5030625, and 5 studies on rs1801552. The pooled results showed that rs16260 was remarkably associated with an increased GC risk of GC among Caucasians. Moreover, the rs5030625 variation dramatically enhanced GC predisposition in the Asian population. However, no evident correlations between CDH1 rs3743674 and rs1801552 polymorphisms and GC risk were observed. CONCLUSIONS Our findings suggested that CDH1 gene polymorphisms were significantly correlated with GC risk, especially in rs16260 and rs5030625 polymorphisms.
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Affiliation(s)
- Qiqi Jiang
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Peizhen Geng
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
| | - Yuying Zhang
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Maoquan Yang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
| | - Jiafeng Zhu
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
| | - Mingwei Zhang
- Department of Pathology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, China
| | - Yamei Wang
- Department of Occupational Diseases, Weifang People’s Hospital, The First Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yikuan Feng
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Xiaojuan Sun
- Department of Occupational Diseases, Weifang People’s Hospital, The First Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
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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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Hugen S, Thomas RE, German AJ, Burgener IA, Mandigers PJJ. Gastric carcinoma in canines and humans, a review. Vet Comp Oncol 2016; 15:692-705. [PMID: 27549077 DOI: 10.1111/vco.12249] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 05/06/2016] [Accepted: 05/20/2016] [Indexed: 02/06/2023]
Abstract
Gastric carcinoma (GC) is the most common neoplasm in the stomach of dogs. Although incidence in the general population is reported to be low, breed-specific GC has a high incidence. Median age at presentation ranges from 8 to approximately 10 years. The disease is mostly located in the lesser curvature and antropyloric region of the stomach. Unfortunately, diagnosis is usually made when the disease is at an advanced stage and, therefore, prognosis is poor. Due to similarities in clinical presentation, diagnosis, histology and prognosis, canine GC may serve as a valuable model for human GC. Extensive pedigrees of canine gastric carcinoma cases could reveal insights for human gastric carcinoma. Putative species differences include the role of Helicobacter in pathogenesis, the wide array of genetic data and screening available for humans, and treatment protocols that are available for human GC.
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Affiliation(s)
- S Hugen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - R E Thomas
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - A J German
- School of Veterinary Science, University of Liverpool, Neston, UK
| | - I A Burgener
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - P J J Mandigers
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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Jiang B, Zhu K, Shao H, Bao C, Ou J, Sun W. Lack of association between the CDH1 polymorphism and gastric cancer susceptibility: a meta-analysis. Sci Rep 2015; 5:7891. [PMID: 25599647 PMCID: PMC4298742 DOI: 10.1038/srep07891] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/16/2014] [Indexed: 01/07/2023] Open
Abstract
E-Cadherin (CDH1) plays a key role in cell adhesion, which is vital to the normal development and maintenance of cells. Down regulation of CDH1, may lead to dysfunction of the cell-cell adhesion system, resulting in increased susceptibility to tumor development and subsequent tumor cell invasion and metastasis. The CDH1 C-160A polymorphism could decrease its transcription efficiency and may increase susceptibility to cancer development, but its relevance to gastric cancer is generally disputed. Consequently, we performed a meta-analysis of published case-control studies, including 4218 gastric cancer cases and 5461 controls. Overall, no significant association was observed between the CDH1 C-160A polymorphism and risk of gastric cancer in all genetic models. In the stratified analysis by total sample size, a significant association was observed in the small sample size subgroup (total sample size < 300), but the results should be interpreted with caution. In conclusion, this meta-analysis failed to confirm the association between the CDH1 C-160A polymorphism and risk of gastric cancer. Large-scale and well-designed studies are needed to confirm our findings.
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Affiliation(s)
- Benchun Jiang
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
| | - Ke Zhu
- Department of Hematology, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
| | - Hua Shao
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
| | - Chenhui Bao
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
| | - Jinlei Ou
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
| | - Wei Sun
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning, China
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Jing H, Dai F, Zhao C, Yang J, Li L, Kota P, Mao L, Xiang K, Zheng C, Yang J. Association of genetic variants in and promoter hypermethylation of CDH1 with gastric cancer: a meta-analysis. Medicine (Baltimore) 2014; 93:e107. [PMID: 25340495 PMCID: PMC4616322 DOI: 10.1097/md.0000000000000107] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is a common cause of cancer-related death. The etiology and pathogenesis of GC remain unclear, with genetic and epigenetic factors playing an important role. Previous studies investigated the association of GC with many genetic variants in and promoter hypermethylation of E-cadherin gene (CDH1), with conflicting results reported.To clarify this inconsistency, we conducted updated meta-analyses to assess the association of genetic variants in and the promoter hypermethylation of CDH1 with GC, including C-160A (rs16260) and other less-studied genetic variants,Data sources were PubMed, Cochrane Library, Google Scholar, Web of Knowledge, and HuGE, a navigator for human genome epidemiology.Study eligibility criteria and participant details are as follows: studies were conducted on human subjects; outcomes of interest include GC; report of genotype data of individual genetic variants in (or methylation status of) CDH1 in participants with and without GC (or providing odds ratios [OR] and their variances).Study appraisal and synthesis methods included the use of OR as a measure of the association, calculated from random effects models in meta-analyses. We used I for the assessment of between-study heterogeneity, and publication bias was assessed using funnel plot and Egger test.A total of 33 studies from 30 published articles met the eligibility criteria and were included in our analyses. We found no association between C-160A and GC (OR = 0.88; 95% confidence interval [CI], 0.71-1.08; P = 0.215), assuming an additive model (reference allele C). C-160A was associated with cardia (OR = 0.21; 95% CI, 0.11-0.41; P = 2.60 × 10), intestinal (OR = 0.66; 95% CI, 0.49-0.90; P = 0.008), and diffuse GC (OR = 0.57; 95% CI, 0.40-0.82; P = 0.002). The association of C-160A with noncardia GC is of bottom line significance (OR = 0.65; 95% CI, 0.42-1.01; P = 0.054). Multiple other less-studied genetic variants in CDH1 also exhibited association with GC. Gene-based analysis indicated a significant cumulative association of genetic variants in CDH1 with GC (all Ps <10). Sensitivity analysis excluding studies not meeting Hardy-Weinberg equilibrium (HWE) yielded similar results. Analysis by ethnic groups revealed significant association of C-160A with cardia GC in both Asian and whites, significant association with noncardia GC only in Asians, and no significant association with intestinal GC in both ethnic groups. There was significant association of C160-A with diffuse GC in Asians (P = 0.011) but not in whites (P = 0.081). However, after excluding studies that violate HWE, this observed association is no longer significant (P = 0.126). We observed strong association of promoter hypermethylation of CDH1 with GC (OR = 12.23; 95% CI, 8.80-17.00; P = 1.42 × 10), suggesting that epigenetic regulation of CDH1 could play a critical role in the etiology of GC.Limitations of this study are as follows: we could not adjust for confounding factors; some meta-analyses were based on a small number of studies; sensitivity analysis was limited due to unavailability of data; we could not test publication bias for some meta-analyses due to small number of included studies.We found no significant association of the widely studied genetic variant C-160A, but identified some other genetic variants showing significant association with GC. Future studies with large sample sizes that control for confounding risk factors and/or intensively interrogate CpG sites in CDH1 are needed to validate the results found in this study and to explore additional epigenetic loci that affect GC risk.
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Affiliation(s)
- Huiquan Jing
- Institute of Social Science Survey (HJ), Peking University, Beijing; Department of Social Science (HJ), Shenyang Medical College; Emergency Department (LL); Department of Gastroenterology (CZ), Shengjing Hospital, China Medical University, Shenyang, Liaoning; Division of Gastroenterology (FD, JY, LM), Second Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi; Department of General Surgery (KX), Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Brain Tumor Center (CZ), Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Biostatistics and Epidemiology (PK), University of Oklahoma Health Sciences Center, Oklahoma City, OK; Rush Alzheimer's Disease Center (JYY); and Department of Neurological Sciences (JYY), Rush University Medical Center, Chicago, IL
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Regulatory Variants and Disease: The E-Cadherin -160C/A SNP as an Example. Mol Biol Int 2014; 2014:967565. [PMID: 25276428 PMCID: PMC4167656 DOI: 10.1155/2014/967565] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 08/23/2014] [Accepted: 08/25/2014] [Indexed: 01/04/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) occurring in noncoding sequences have largely been ignored in genome-wide association studies (GWAS). Yet, amounting evidence suggests that many noncoding SNPs especially those that are in the vicinity of protein coding genes play important roles in shaping chromatin structure and regulate gene expression and, as such, are implicated in a wide variety of diseases. One of such regulatory SNPs (rSNPs) is the E-cadherin (CDH1) promoter -160C/A SNP (rs16260) which is known to affect E-cadherin promoter transcription by displacing transcription factor binding and has been extensively scrutinized for its association with several diseases especially malignancies. Findings from studying this SNP highlight important clinical relevance of rSNPs and justify their inclusion in future GWAS to identify novel disease causing SNPs.
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Deng QW, He BS, Pan YQ, Sun HL, Xu YQ, Gao TY, Li R, Song GQ, Wang SK. Roles of E-Cadherin (CDH1) Genetic Variations in Cancer Risk: a Meta-analysis. Asian Pac J Cancer Prev 2014; 15:3705-13. [DOI: 10.7314/apjcp.2014.15.8.3705] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Chu CM, Chen CJ, Chan DC, Wu HS, Liu YC, Shen CY, Chang TM, Yu JC, Harn HJ, Yu CP, Yang MH. CDH1 polymorphisms and haplotypes in sporadic diffuse and intestinal gastric cancer: a case-control study based on direct sequencing analysis. World J Surg Oncol 2014; 12:80. [PMID: 24684952 PMCID: PMC4230630 DOI: 10.1186/1477-7819-12-80] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 02/10/2014] [Indexed: 12/13/2022] Open
Abstract
Background Findings related to the influence of the −160C → A promoter polymorphism and haplotypes of the E-cadherin (CDH1) gene have not been consistent in previous studies regarding the risk for sporadic gastric cancer. Investigators in most previous studies detected those genotypes using restriction fragment length polymorphism analysis. Therefore, we conducted a case–control study to investigate the association of the CDH1 − 160C → A promoter polymorphism and haplotypes for cancer risk related to sporadic diffuse and intestinal gastric cancer by direct sequencing analysis. Methods We included 107 diffuse gastric cancer cases, 60 intestinal gastric cancer cases and 134 controls. The genotypic polymorphisms in the −160 promoter region, exons and intron–exon boundaries of CDH1 were detected by direct sequencing analysis. Genotype frequencies were compared. The CDH1 − 160C → A promoter polymorphism and four polymorphisms (48 + 6 T → C, 2076C → T, 2253C → T and 1937–13 T → C) were included in the haplotype analyses, which were estimated using the expectation–maximization algorithm. Results Compared to controls, the frequency of the −160A allele was significantly higher in diffuse gastric cancer cases (P = 0.005), but it was not significantly different in intestinal gastric cancer cases (P = 0.119). Two sets of three-marker haplotypes (−160C → A, 48 + 6 T → C, 2076C → T and −160C → A, 1937–13 T → C, 2253C → T) were associated with the risk of diffuse gastric cancer (P = 0.011 and P = 0.042, respectively). Conclusion Based on direct sequencing analysis, our findings suggest that the CDH1 − 160C → A promoter polymorphism and haplotypes play significant roles in cancer risk for sporadic diffuse gastric cancer, but not for intestinal gastric cancer, in a Taiwanese population.
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Affiliation(s)
| | | | | | | | - Yao-Chi Liu
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No, 325, Sec, 2, Cheng-Kung Road, Neihu, Taipei 11490, Taiwan.
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9
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Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. E-cadherin alterations in hereditary disorders with emphasis on hereditary diffuse gastric cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2013; 116:337-59. [PMID: 23481202 DOI: 10.1016/b978-0-12-394311-8.00015-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
The only gastric cancer (GC) syndrome with a proven inherited defect is designated as hereditary diffuse gastric cancer (HDGC) and is caused by germline E-cadherin/CDH1 alterations. Other E-cadherin-associated hereditary disorders have been identified, encompassing HDGC families with or without cleft-lip/palate involvement, isolated early-onset diffuse GCs, and lobular breast cancer families without GC. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described in these different settings. A third of all HDGC families described so far carry recurrent CDH1 alterations. Full screening of CDH1 is recommended in patients fulfilling the HDGC criteria and total prophylactic gastrectomy is the only reliable intervention for carriers of pathogenic alterations. In this chapter, we discuss CDH1-associated syndromes, frequency and type of CDH1 germline alterations, clinical criteria, and guidelines for genetic counseling, molecular pathology, and available animal/cell line models of the disease.
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Affiliation(s)
- Carla Oliveira
- Expression Regulation in Cancer Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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Contribution of the -160C/A polymorphism in the E-cadherin promoter to cancer risk: a meta-analysis of 47 case-control studies. PLoS One 2012; 7:e40219. [PMID: 22792244 PMCID: PMC3390351 DOI: 10.1371/journal.pone.0040219] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 06/02/2012] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The -160C/A polymorphism (rs16260) of E-cadherin, a tumor repressor gene, has been shown to be a tumor susceptibility allele for various types of cancers. Because the significance of this polymorphism to cancer risk has been recognized, there are increasing studies investigating -160C/A in different types of cancers and ethnic populations. However, there is still uncertainty about the level of risk for a variety of cancers. METHODS To resolve the controversial question raised by these studies as of March 2012 and provide more statistical power for detecting the significance of -160C/A, we performed a meta-analysis of 47 case-control studies in 16 types of cancers (18,194 cases and 20,207 controls). A meta-regression model and subgroup analysis were employed to identify the source of heterogeneity. Publication bias was evaluated, and sensitivity analysis and cumulative evidence assessment were also performed. RESULTS Using fixed- and random-effects models, the -160AA homozygote was more susceptible to urothelial cancer compared with the -160CA heterozygote. Additionally, the -160A allele is an ethnicity-dependent risk factor for prostate and colorectal cancers. Carriers of the -160A allele in Asians and Europeans were more susceptible to prostate cancer, whereas their North American counterparts seemed tolerant. The -160AA homozygote plays a protective role for Europeans who develop colorectal cancer. The stability of these observations was confirmed by a one-way sensitivity analysis. However, the cumulative evidence for all cancer types was considered 'weak' using the Venice guidelines. CONCLUSIONS A meta-analysis indicated that the -160A allele of E-cadherin provides a higher risk for the development of prostate and urothelial cancers and a protective role for colorectal cancer in an ethnicity-dependent manner.
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Wang Q, Gu D, Wang M, Zhang Z, Tang J, Chen J. The E-cadherin (CDH1) −160C>A Polymorphism Associated with Gastric Cancer Among Asians But Not Europeans. DNA Cell Biol 2011; 30:395-400. [PMID: 21214416 DOI: 10.1089/dna.2010.1091] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Affiliation(s)
- Qiong Wang
- Department of Oncology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Wuxi, P.R. China
| | - Dongying Gu
- Department of Oncology, The Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Meilin Wang
- Department of General Surgery, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Zhengdong Zhang
- Department of General Surgery, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Jinhai Tang
- Department of Molecular & Genetic Toxicology, School of Public Health, Nanjing Medical University, Nanjing, P.R. China
| | - Jinfei Chen
- Department of Oncology, The Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
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Li YL, Tian Z, Zhang JB, Fu BY. CDH1 promoter polymorphism and stomach cancer susceptibility. Mol Biol Rep 2011; 39:1283-6. [PMID: 21625863 DOI: 10.1007/s11033-011-0860-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 05/12/2011] [Indexed: 12/18/2022]
Abstract
The relationship of stomach cancer susceptibility and the presence of E-cadherin (CDH1) promoter -160 C/A polymorphism had been reported with conflicting results. To further explore the association of this polymorphism with stomach cancer susceptibility, we performed an extensive search of relevant studies and carried out a meta-analysis to obtain a more precise estimate. A total of 16 studies including 2,611 cases and 3,788 controls were involved in this meta-analysis. When all studies involved, the meta-analysis results suggest no statistically significant association between CDH1 -160 C/A polymorphism and stomach cancer risk (CA vs. CC: OR = 1.01, 95% CI: 0.85-1.19; AA vs. CC: OR = 1.05, 95% CI: 0.75-1.46; dominant model: OR = 1.02, 95% CI: 0.86-1.20; recessive model: OR = 1.04, 95% CI: 0.76-1.41). When subgroup analyses were performed by ethnicity, the A-allele carriers conferred a decreased stomach cancer risk in Asians (AA vs. CC: OR = 0.67, 95% CI: 0.47-0.96; dominant model: OR = 0.85, 95% CI: 0.72-0.99), but no statistically significant association was found in Caucasians. In conclusion, this meta-analysis suggests that CDH1 -160 A-allele may play a protective role of stomach cancer development in Asians but not in Caucasians.
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Affiliation(s)
- Yi-Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China.
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Cui Y, Xue H, Lin B, Ni P, Fang JY. A meta-analysis of CDH1 C-160A genetic polymorphism and gastric cancer risk. DNA Cell Biol 2011; 30:937-45. [PMID: 21612411 DOI: 10.1089/dna.2011.1257] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We explored the role of the C-160A single-nucleotide polymorphism (SNP) of CDH1 in susceptibility to gastric cancer through a systematic review and meta-analysis. Fourteen studies were included, the original groups collapsed, and re-grouped in accordance with the most appropriate genetic model. Potential sources of heterogeneity were sought out via subgroup analyses and sensitivity analyses, and publication biases were estimated. No significant association of C-160A was found with the overall risk of developing gastric cancer, but the apparently opposite tendency was noted between Caucasians and Asians, and a statistically significant association was found among Asians. The seemingly opposite tendency of associations was also seen between noncardia and cardia types or between sporadic diffuse and intestinal types of gastric cancer, but no statistically significant findings were noted. Genotyping techniques, sample size, quality appraisal scores, or article publication time did not constitute the source of heterogeneity across studies; and no publication biases were found in our meta-analysis.
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Affiliation(s)
- Yun Cui
- Department of Gastroenterology, Renji Hospital, Shanghai Institute of Gastrointestinal Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
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Chen B, Zhou Y, Yang P, Liu L, Qin XP, Wu XT. CDH1 -160C>A gene polymorphism is an ethnicity-dependent risk factor for gastric cancer. Cytokine 2011; 55:266-73. [PMID: 21570316 DOI: 10.1016/j.cyto.2011.04.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 03/19/2011] [Accepted: 04/15/2011] [Indexed: 02/05/2023]
Abstract
The associations between E-cadherin (CDH1) gene polymorphisms and gastric cancer (GC) susceptibility are still controversial. Given this uncertainty, we carried out a meta-analysis of published case-control studies to derive more precise estimations of these relationships. Relevant studies were identified from PubMed and EMBASE up to March 2011. Seventeen studies with 3511 GC cases and 4826 controls were selected. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to investigate the strength of the associations. No associations between CDH1 (+54T>C, -160C>A, -347G>GA, -616G>C, -2076C>T and -3159T>C) gene polymorphisms and GC risk for all genetic models were found. As for CDH1 -160C>A polymorphism, subgroup analyses by country, gender, study design, smoking status, Helicobacter pylori infection, and the Lauren classification of GC did not change the results. When stratified by ethnicity, we found the A allele carriers had a significantly increased risk of GC among Caucasians (AA vs. CA+CC: OR=1.50, 95% CI=1.03-2.19, P=0.03), but not among Asians (AA vs. CA+CC: OR=0.87, 95% CI=0.56-1.37, P=0.56). No publication bias was found in the present study. This meta-analysis suggests that CDH1 -160C>A gene polymorphism may contribute to increased risk of GC among Caucasians.
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Affiliation(s)
- Bo Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Al-Moundhri MS, Al-Khanbashi M, Al-Kindi M, Al-Nabhani M, Burney IA, Al-Farsi A, Al-Bahrani B. Association of E-cadherin ( CDH1) gene polymorphisms and gastric cancer risk. World J Gastroenterol 2010; 16:3432-6. [PMID: 20632448 PMCID: PMC2904892 DOI: 10.3748/wjg.v16.i27.3432] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the associations between CDH1 gene polymorphisms and gastric cancer (GC) risk predisposition.
METHODS: We analyzed four CDH1 polymorphisms (+54 T>C, -160 C>A, -616 G>C, -3159 T>C) in an Omani population, by extraction of genomic DNA from the peripheral blood of 192 patients with GC and 170 control participants and performed CDH1 genotyping using DNA sequencing.
RESULTS: CDH1 -160 -AA genotype was associated with an increased risk of GC (OR = 3.6, 95% CI: 1.1-11.8) (P = 0.03). There was no significant association between the other polymorphisms and GC risk. The haplotype analysis of +54 T>C, -160 C>A, -616 G>C, -3159 T>C genotypes revealed that the OR of CCGC and CAGC haplotypes was 1.5 (95% CI: 0.7-3.5) and 1.5 (95% CI: 0.2-3.0), but did not reach statistical significance.
CONCLUSION: The current study suggests that the -160 AA genotype was associated with an increased risk of GC in Oman.
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Cao WJ, Zhang ZY, Yue QY. CDH1 C-160A promoter polymorphism and genetic susceptibility to gastric cancer: a meta-analysis. Shijie Huaren Xiaohua Zazhi 2010; 18:1270-1274. [DOI: 10.11569/wcjd.v18.i12.1270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between E-cadherin (CDH1) gene C-160A promoter polymorphism and genetic susceptibility to gastric cancer.
METHODS: Chinese biomedicine disc (CBM), Wanfang database, China National Knowledge Infrastructure (CNKI) and PubMed were searched for published case-control studies investigating the association between CDH1 C-160A promoter polymorphism and susceptibility to gastric cancer. The odds ratio was calculated to evaluate the genotypes of gastric cancer patients and control subjects. Fixed or random effect models were selected for pooled odds ratio calculation. Publication bias was assessed. All statistical analyses were conducted with Stata 10.0 software.
RESULTS: A total of 14 case-control studies involving 3 144 gastric cancer patients and 4 221 controls were analyzed in the study. Compared with the wild-type genotype (homozygote CC), the pooled odds ratio [and 95% confidence interval (CI)] for CA and AA genotypes was 0.98 (0.84-1.15). In the population subgroup analysis, the odds ratios for Asian and Caucasian populations were 0.92 (0.81-1.04) and 1.21 (0.88-1.67), respectively.
CONCLUSION: CDH1 C-160A promoter polymorphism is not associated with genetic susceptibility to gastric cancer.
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Fei Y, Hu J, Liu S, Liu X, Wang F, Gong J. E-cadherin-160 C/A promoter polymorphism and risk of pancreatic carcinoma in Chinese population. ACTA ACUST UNITED AC 2010; 197:25-31. [PMID: 20113833 DOI: 10.1016/j.cancergencyto.2009.10.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 10/19/2009] [Accepted: 10/24/2009] [Indexed: 12/11/2022]
Abstract
Recent studies have implicated E-cadherin-160C/A single-nucleotide polymorphism (SNP) in susceptibility to and early onset of some cancers. We investigated the role of E-cadherin-160 C/A SNP in Chinese pancreatic carcinoma patients without dominant family history by genotyping 254 patients and 101 controls. The risk of cancer for CC genotype individuals was less than half that of AA individuals [odds ratio (OR) = 0.41; 95%confidence interval (95%CI) = 0.18-0.96]. Furthermore, patients with the CC and CA genotypes whose tumors were stages III (T(4)N(x)M(0)) and IV (T(x)N(x)M(1)) (OR = 0.38; 95%CI = 0.17-0.83), poorly differentiated (OR = 0.28; 95%CI = 0.09-0.84), and left-sided (OR = 0.45; 95%CI 0.21-0.98) were associated with significantly lower risk than AA patients. Young (60 years old or younger) AA patients had a 5-year lower mean age at onset than CC/CA patients (P = 0.02). Young male AA patients had worse disease-specific survival than CC/CA patients (P = 0.002). Thus, contrary to Canadians and Portuguese, the AA (rather than CC) genotype is associated with increased susceptibility and advanced pancreatic carcinoma in Chinese patients, suggesting a more complex relationship between the SNP and pancreatic carcinoma risk, possibly modulated by population differences.
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Affiliation(s)
- Yang Fei
- Department of General Surgery, The 81st hospital of P.L.A., P.L.A. Cancer Center, Nanjing, P.R. China.
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Loh M, Koh KX, Yeo BH, Song CM, Chia KS, Zhu F, Yeoh KG, Hill J, Iacopetta B, Soong R. Meta-analysis of genetic polymorphisms and gastric cancer risk: variability in associations according to race. Eur J Cancer 2009; 45:2562-8. [PMID: 19375306 DOI: 10.1016/j.ejca.2009.03.017] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 03/12/2009] [Accepted: 03/17/2009] [Indexed: 01/06/2023]
Abstract
The goal of this study was to consolidate information on genetic risk factors for gastric cancer. An additional aim was to investigate the influence of race on these genetic risk associations. Relevant studies were identified from PubMed and references of retrieved articles. Meta-analysis techniques were used to summarise associations between genetic polymorphisms and gastric cancer. A total of 203 relevant studies were identified, assessing 225 polymorphisms across 95 genes. Subgroup analysis indicated that Chinese, Japanese and Korean data were consistent and could be pooled. However, 6 of 13 polymorphisms (ACE I/D, CCND1 870G>A, CDH1 -160C>A, IL1B -511C>T, IL4 -590C>T, IL10 -592A>C) displayed conflicting effects between Asian and Caucasian populations, three of which (ACE I/D, CCND1 870G>A, IL1B -511C>T) had significantly different odds ratios between the two racial groups. In total, 37 polymorphisms across 27 genes were found to be significantly associated with gastric cancer in Asians, and 12 polymorphisms across 11 genes in Caucasians. Consolidated panels of polymorphisms associated with gastric cancer risk were identified in Asians and Caucasians. The results caution against the assumption that genetic risk factors are consistent between races.
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Affiliation(s)
- Marie Loh
- Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Center of Life Science Level 2, Singapore 117456, Singapore
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19
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Abstract
The objective of this study was to find out whether C-160A single nucleotide polymorphism of the promoter region of the E-cadherin gene might be a potential genetic marker for identifying individuals at risk for gastric cancer (GC). To test this hypothesis, 412 GC patients and 408 controls were analyzed statistically. A PCR-restriction fragment length polymorphism assay was adopted for C-160A single nucleotide polymorphism detection. No statistical differences were found among CC, CA, and AA genotypes and the risk of GC, even stratifying according to age, sex, and area of residence. Similarly, genotype was not associated with intestinal or diffuse histotypes, or with cardia or noncardia carcinomas. In conclusion, the C-160A polymorphism is not associated with GC risk in the Italian population.
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20
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Genetic Polymorphisms of the E-Cadherin Promoter and Risk of Sporadic Gastric Carcinoma in Chinese Populations. Cancer Epidemiol Biomarkers Prev 2008; 17:2402-8. [DOI: 10.1158/1055-9965.epi-08-0315] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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21
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Gao L, Nieters A, Brenner H. Meta-analysis: tumour invasion-related genetic polymorphisms and gastric cancer susceptibility. Aliment Pharmacol Ther 2008; 28:565-73. [PMID: 18544073 DOI: 10.1111/j.1365-2036.2008.03760.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Host genetic susceptibility has been suggested as one of the most important possible explanations for interindividual difference in gastric cancer (GC) risk. AIM To evaluate the impact of tumour invasion-related gene polymorphisms, which may be involved in a variety of processes during GC development, such as cell adhesion and angiogenesis, on the risk of GC. METHODS We reviewed published studies on tumour invasion-related gene polymorphisms and GC susceptibility until 31 March 2008, and then quantitatively summarized associations of the most widely-studied polymorphism, CDH1 -160C>A, with GC using meta-analysis. RESULTS Twenty-seven eligible studies were included in this review. Fourteen polymorphisms significantly related to GC in at least one study were identified. For several polymorphisms, heterogeneous results were observed and associations in opposite directions were seen among Asian and Caucasian populations. In meta-analysis, CDH1 -160C>A showed an inverse association with GC among Asians (OR, 0.76; 95% CI, 0.55-1.05) and a positive association among Caucasians (OR, 1.40; 95% CI, 0.95-2.04). CONCLUSIONS This review suggests that genetic polymorphisms in tumour invasion could be candidate biomarkers of GC risk. However, differences between populations and stages of cancer need to be taken into account and may explain some of the inconsistencies found in previous studies.
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Affiliation(s)
- L Gao
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
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22
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Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, Saito D, Sugimura H, Tanioka F, Kato S, Matsukura N, Matsuda N, Nakamura T, Hyodo I, Nishina T, Yasui W, Hirose H, Hayashi M, Toshiro E, Ohnami S, Sekine A, Sato Y, Totsuka H, Ando M, Takemura R, Takahashi Y, Ohdaira M, Aoki K, Honmyo I, Chiku S, Aoyagi K, Sasaki H, Ohnami S, Yanagihara K, Yoon KA, Kook MC, Lee YS, Park SR, Kim CG, Choi IJ, Yoshida T, Nakamura Y, Hirohashi S. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet 2008; 40:730-40. [PMID: 18488030 DOI: 10.1038/ng.152] [Citation(s) in RCA: 327] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2007] [Accepted: 03/26/2008] [Indexed: 12/14/2022]
Abstract
Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.
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23
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Nasri S, More H, Graziano F, Ruzzo A, Wilson E, Dunbier A, McKinney C, Merriman T, Guilford P, Magnani M, Humar B. A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: a case control study in an Italian population. BMC Cancer 2008; 8:138. [PMID: 18482459 PMCID: PMC2412889 DOI: 10.1186/1471-2407-8-138] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Accepted: 05/15/2008] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Inherited genetic factors such as E-cadherin (CDH1) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for CDH1 transcription has been identified in CDH1 intron 2. METHODS We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using chi2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis. RESULTS We observed a significant (p < 0.0004) association of the CDH1 163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09-9.93) and 1.38 (95%CI = 0.75-2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H. pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied. CONCLUSION The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.
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Affiliation(s)
- Soroush Nasri
- Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin 9054, Aotearoa New Zealand.
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24
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Tan XL, Nieters A, Kropp S, Hoffmeister M, Brenner H, Chang-Claude J. The association of cyclin D1 G870A and E-cadherin C-160A polymorphisms with the risk of colorectal cancer in a case control study and meta-analysis. Int J Cancer 2008; 122:2573-80. [PMID: 18196581 DOI: 10.1002/ijc.23363] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Cyclin D1 (CCND1) and E-cadherin (CDH1) have been shown to be important genes of the beta-catenin/LEF pathway that is involved in colorectal carcinogenesis. However, epidemiological studies on relationship between genetic variants of these two genes and colorectal cancer (CRC) have shown inconsistent results. In a population-based case-control study (498 cases and 600 controls), we assessed the association of CCND1 G870A and CDH1 C-160A polymorphisms with CRC risk. Multivariable logistic regression analysis was used to estimate the association between genotypes, environmental exposures and CRC risk, adjusting for potential confounders. Compared to common homozygotes, the OR for heterozygous and homozygote variant genotype was 1.08 (95% CI, 0.80-1.46) in CCND1 and 0.97 (95% CI, 0.75-1.25) in CDH1. Neither tumor stage nor location showed an association with genetic susceptibility. However, a significant interaction between hormone replacement therapy (HRT) and CCND1 genotypes in CRC risk was found among postmenopausal women (p(interaction) = 0.02). The risk reduction associated with HRT was substantial (OR, 0.09; 95% CI, 0.02-0.35) in women who were GG homozygous. A meta-analyses including 11 published studies on CCND1 G870A in addition to our study showed a slightly increased risk of CRC for carriers of the A allele (OR, 1.19; 95% CI, 1.06-1.34); however, there was some indication of publication bias. We conclude that the CCND1 G870A and CDH1 C-160A polymorphisms are not associated with the risk of CRC in the German population. However, the CCND1 G870A polymorphism may modify the protective effect of postmenopausal hormone use on the development of CRC.
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Affiliation(s)
- Xiang-Lin Tan
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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25
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Jenab M, McKay JD, Ferrari P, Biessy C, Laing S, Munar GMC, Sala N, Peña S, Crusius JBA, Overvad K, Jensen MK, Olsen A, Tjonneland A, Clavel-Chapelon F, Boutron-Ruault MC, Kaaks R, Linseisen J, Boeing H, Bergmann MM, Trichopoulou A, Georgila C, Psaltopoulou T, Mattiello A, Vineis P, Pala V, Palli D, Tumino R, Numans ME, Peeters PHM, Bueno-de-Mesquita HB, Lund E, Ardanaz E, Sánchez MJ, Dorronsoro M, Sanchez CN, Quirós JR, Hallmans G, Stenling R, Manjer J, Régner S, Key T, Bingham S, Khaw KT, Slimani N, Rinaldi S, Boffetta P, Carneiro F, Riboli E, Gonzalez C. CDH1 gene polymorphisms, smoking, Helicobacter pylori infection and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Eur J Cancer 2008; 44:774-80. [PMID: 18342503 DOI: 10.1016/j.ejca.2008.02.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Revised: 01/29/2008] [Accepted: 02/05/2008] [Indexed: 02/06/2023]
Abstract
Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. E-Cadherin is an adhesion molecule that is thought to be involved in GC. Germline mutations in the E-Cadherin gene (CDH1) have been identified in hereditary diffuse GC. Also, a promoter polymorphism at position -160 C/A has been suggested to lead to transcriptional down regulation and has been shown to affect GC risk in some studies. However, very little information exists on the GC risk association of other CDH1 polymorphisms and it is unclear whether any associations may be different by GC anatomical sites or histological types. Thus, a case-control study (cases=245/controls=950) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was conducted to assess the GC risk association of eight CDH1 gene polymorphisms. None of the CDH1 polymorphisms or haplotypes analysed were associated with GC risk and no differences of effect were observed by Helicobacter pylori infection status. However, three CDH1 polymorphisms in the same haplotype block, including the CDH1-160C/A, interacted with smoking to increase GC risk in smokers but not in never smokers. These findings should be confirmed in larger independent studies.
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Affiliation(s)
- Mazda Jenab
- International Agency for Research on Cancer (IARC-WHO), Lyon, France.
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Zhang XF, Wang YM, Ge H, Cao YY, Chen ZF, Wen DG, Guo W, Wang N, Li Y, Zhang JH. Association of CDH1 single nucleotide polymorphisms with susceptibility to esophageal squamous cell carcinomas and gastric cardia carcinomas. Dis Esophagus 2008; 21:21-9. [PMID: 18197935 DOI: 10.1111/j.1442-2050.2007.00724.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
E-cadherin (CDH1) is a tumor suppressor involved in epithelial cell-cell interactions. Single nucleotide polymorphisms (SNP) in the CDH1 gene, -160C/A and -347G/GA in the 5'-promoter region and +54C/T in the 3'-untranslated region (UTR) have been shown to be associated with tumor development and progression via modifying transcriptional activity, mRNA stability or protein expression. To investigate the influence of CDH1 SNP on susceptibility to esophageal squamous cell carcinomas (ESCC) and gastric cardia adenocarcinomas (GCA), a case-control study was conducted among 333 ESCC patients, 239 GCA patients and 343 controls from a northern Chinese population. CDH1 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The results showed that; (i) genotypes with the +54C allele (C/C or C/T) significantly increased the risk of developing both ESCC and GCA compared to the +54T/T genotype (age and gender adjusted odds ratio [OR] = 1.45 and 2.28, 95% confidence interval [CI] = 1.06-1.99 and 1.58-3.30, respectively), and this association was significant only among non-smokers (OR = 1.68 and 2.64, 95% CI = 1.01-2.80 and 1.43-4.87 for ESCC and GCA, respectively), and individuals without a family history of upper gastrointestinal cancer (OR = 2.63 and 2.97, 95% CI = 1.36-5.10 and 95% CI = 1.32-6.68 for ESCC and GCA, respectively); (ii) compared with the -347G/G genotype, the -347GA and GA/GA genotypes significantly increased the risk of developing GCA (OR = 1.45, 95 % CI = 1.03-2.04); (iii) there was a significant association of CDH1-160C/-347G/+54C and -160C/-347GA/+54C haplotypes with the development of GCA, compared with the -160C/-347G/+54T haplotype (OR = 1.80 and 2.21, 95% CI = 1.33-2.44 and 1.43-3.42, respectively); and (iv) the influence of CDH1 SNP on the depth of tumor invasion and lymphatic metastasis in ESCC and GCA patients was not observed in this study. The present study indicates that CDH1 polymorphisms might modify susceptibility to ESCC and/or GCA.
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Affiliation(s)
- X-F Zhang
- Hebei Cancer Institute and the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang Hebei Province, China
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27
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Yamada H, Shinmura K, Ikeda S, Tao H, Otani T, Hanaoka T, Tsuneyoshi T, Tsugane S, Sugimura H. Association between CDH1 haplotypes and gastric cancer risk in a Japanese population. Scand J Gastroenterol 2007; 42:1479-85. [PMID: 17852867 DOI: 10.1080/00365520701478436] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE A c. -285C >A single nucleotide polymorphism (SNP) in the promoter region of the E-cadherin (CDH1) gene, which is a tumor suppressor in gastric cancer (GC), has been shown to decrease gene transcription, but GC case-control studies of this SNP have yielded controversial results. A haplotype study in an Italian population showed that haplotypes based on three SNPs, including the c. -285C >A, are associated with susceptibility to GC. Hence, the purpose of the present study was to carry out a more comprehensive genetic analysis of CDH1 using haplotype-tagging SNPs (htSNPs) in a Japanese case-control study to identify the CDH1 haplotype associated with susceptibility to GC in a Japanese population. MATERIAL AND METHODS First, 11 SNPs in the CDH1 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 30 healthy individuals. Haplotype frequencies were estimated with the expectation-maximization algorithm, and 7 common haplotypes of the CDH1 gene whose frequency was at least 3.3% were identified. Next, 5 htSNPs (c. -285C >A, c.48+6T >C, c.164 -3159T >C, c.2076C >T, and c.2296 -616G >C) were genotyped in a hospital-based case-control study of 148 GC patients and 292 age- and gender-matched healthy controls, and haplotype frequencies based on the 5 htSNPs were estimated. RESULTS Although none of the 5 htSNPs was related to an overall risk of GC, frequencies of the ATCTG and CTTTG haplotypes were significantly higher and lower, respectively, in the GC cases than in the controls (p<0.05). CONCLUSIONS These results suggest that the ATCTG and CTTTG CDH1 haplotypes may be associated with an increased risk and decreased risk, respectively, of GC in the Japanese population.
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Affiliation(s)
- Hidetaka Yamada
- First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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28
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Medina-Franco H, Ramos-De la Medina A, Vizcaino G, Medina-Franco JL. Single nucleotide polymorphisms in the promoter region of the E-cadherin gene in gastric cancer: case-control study in a young Mexican population. Ann Surg Oncol 2007; 14:2246-9. [PMID: 17549573 DOI: 10.1245/s10434-006-9054-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2006] [Accepted: 05/02/2006] [Indexed: 12/27/2022]
Abstract
BACKGROUND Gastric cancer has a tendency to present at early age in the Mexican population, and it is frequently associated with a family history. A polymorphism at position -160 at the CDH1 promoter region has been reported to lead to transcriptional downregulation of the gene in vitro, with possible increase in the risk of gastric cancer. We evaluated the role of the -160A allele in the risk of gastric cancer in a young Mexican population. METHODS Peripheral blood sample of Mexican patients younger than 45 years old with diagnosis of diffuse gastric cancer were obtained. We performed DNA extraction and analyzed the frequencies of -160 promoter polymorphism of E-cadherin gene by polymerase chain reaction-single strand conformational polymorphism. These frequencies were compared with those of healthy controls. The chi2 test for association was used to test differences of the genotype frequencies between normal controls and patients with gastric cancer. Findings were considered significant at P < .05. RESULTS The frequency of the -160 A allele was significantly higher (P = .002) in 39 patients with diffuse gastric cancer compared with 78 matched controls. The odds ratio associated with the A-allele was 1.98 for C/A heterozygotes (95% CI 1.01-3.98) and 6.5 for A/A homozygotes (95% CI 2.1-19.6). We found an increased risk of diffuse gastric cancer according to family history, independent of the expression of the polymorphism. CONCLUSIONS The -160 C/A polymorphism of the E-cadherin has a direct effect on the risk of diffuse gastric cancer at young age in Mexican population.
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Affiliation(s)
- Heriberto Medina-Franco
- Department of Surgery, Section of Surgical Oncology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Vasco de Quiroga 15, Colonia Seccion XVI, Tlalpan, Mexico City, Mexico.
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29
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Li HC, Albert JM, Shinohara ET, Cai Q, Freyer A, Cai H, Cao C, Wang Z, Kataoka N, Teng M, Zheng W, Lu B. E-cadherin promoter polymorphisms are not associated with the aggressiveness of prostate cancer in Caucasian patients. Urol Oncol 2007; 24:496-502. [PMID: 17138130 DOI: 10.1016/j.urolonc.2006.02.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2005] [Revised: 02/08/2006] [Accepted: 02/09/2006] [Indexed: 11/21/2022]
Abstract
BACKGROUND -160C-->A and -347G-->GA polymorphisms in the promoter region decrease E-cadherin gene transcription. Decreased E-cadherin expression predicts poor outcome among patients with cancer. We sought to investigate whether -160C-->A and/or -347G-->GA polymorphisms were associated with the aggressiveness of prostate cancer. METHODS TaqMan single nucleotide polymorphism genotyping assay (Applied Biosystems, Foster City, CA) was used to detect -160C-->A and -347G-->GA polymorphisms in deoxyribonucleic acid from the paraffin-embedded prostate tissues of 98 Caucasian patients. RESULTS The genotype frequencies were -160C/C: 48% (47 of 98); -160C/A: 44% (43 of 98); -160A/A: 8% (8 of 98); -347G/G: 68% (67 of 98); -347G/GA: 28% (27 of 98); and -347GA/GA: 4% (4 of 98). Using the chi-square test, we found that the polymorphisms -160C-->A and -347G-->GA were not related to other clinical and pathologic parameters (i.e., age, prostate-specific antigen level, Gleason grade, and clinical stage) (P > 0.05). In combination analysis, there was no significant relationship between patients with both -160C/C and -347G/G, and these same parameters (P > 0.05). Using the log-rank test, we found no significant difference in relapse-free survival and overall survival between patients with -160C/C and those with -160A/C or -160A/A (P = 0.0764 and 0.2746, respectively), and also no significant difference between patients with -347G/G and those with -347GA/G or -347GA/GA (P = 0.9416 and 0.7367, respectively). There was also no significant difference in relapse-free survival and overall survival between patients with homozygosities of -160C/-347G and patients with other genotypes (P = 0.1418 and 0.2434, respectively). CONCLUSION We conclude that E-cadherin -160C-->A and/or -347G-->GA polymorphisms are not associated with the aggressiveness of prostate cancer in Caucasian patients.
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Affiliation(s)
- He-Cheng Li
- Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Kiemeney LA, van Houwelingen KP, Bogaerts M, Witjes JA, Swinkels DW, den Heijer M, Franke B, Schalken JA, Verhaegh GW. Polymorphisms in the E-cadherin (CDH1) gene promoter and the risk of bladder cancer. Eur J Cancer 2006; 42:3219-27. [PMID: 16934975 DOI: 10.1016/j.ejca.2006.05.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2006] [Accepted: 05/05/2006] [Indexed: 11/19/2022]
Abstract
AIM E-cadherin plays a role in carcinogenesis. For two genetic polymorphisms in the gene (CDH1) promoter, a reduced transcription has been reported: a C/A single nucleotide polymorphism (SNP) and a G/GA SNP at -160 bp and -347 bp, respectively, upstream of the transcriptional start site. We studied the association between both polymorphisms and the risk of bladder cancer. METHODS One hundred and ninety-seven patients with bladder cancer and 344 population controls were genotyped and haplotyped for both SNPs. RESULTS A borderline significantly increased risk for bladder cancer was found for A allele carriers (OR 1.36; 95% CI: 0.96-1.94). We did not find any association between the -347 G/GA SNP and bladder cancer. Haplotype analyses did not yield much stronger associations with bladder cancer than the -160 C/A genotype analyses. CONCLUSION This study supports earlier suggestions that the -160 C/A SNP in the CDH1 promoter is a risk factor for bladder cancer.
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Affiliation(s)
- Lambertus A Kiemeney
- Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
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Abstract
Gastric cancer is relatively common worldwide, mainly in its sporadic form, but familial aggregation of the disease may be seen in approximately 10% of the cases. This suggests a genetic cause for the cancer in those families that has not been identified in most cases. Despite all efforts to determine its genetic basis, a single syndrome has been characterized-the hereditary diffuse gastric cancer (HDGC)-which is specifically associated with CDH1 (E-cadherin) germline mutations in one third of the families. The other two thirds and all the gastric cancer families not fulfilling the HDGC criteria remain without molecular diagnosis. In this article we review the state of the art of familial gastric cancer regarding the molecular aspects, the clinical criteria, the pathology features, and the management recommendations described so far to be associated with this cancer disease.
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Affiliation(s)
- Carla Oliveira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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Bonilla C, Mason T, Long L, Ahaghotu C, Chen W, Zhao A, Coulibaly A, Bennett F, Aiken W, Tullock T, Coard K, Freeman V, Kittles RA. E-cadherin polymorphisms and haplotypes influence risk for prostate cancer. Prostate 2006; 66:546-56. [PMID: 16372334 DOI: 10.1002/pros.20374] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND The E-cadherin (CDH1) gene has been implicated in prostate cancer (PCA) risk, however, the exact mechanism is unknown. Several polymorphisms, such as the C/A variant -160 base pairs from the transcription start site, in the CDH1 gene promoter region have been associated with cancer risk, mainly in European descent populations. METHODS We screened the entire coding region and 3.0 kilobases of the CDH1 promoter for polymorphisms in 48 African Americans using dHPLC. Twenty-one (21) polymorphisms were observed. Four polymorphisms, including -160C/A, were genotyped in a genetic association study using incident PCA cases (N = 427) and unaffected controls (N = 337) of similar age from three different ethnic groups consisting of African Americans, Jamaicans, and European Americans. RESULTS We observed a significantly higher frequency of the -160A allele among European American PCA patients (27.5%) compared to the control group (19.7%) (P = 0.04). More importantly, among men of European ancestry under the age of 65 who possess the -160 A allele there was over three times increased risk for prostate cancer (P = 0.05). Also, the AACT haplotype bearing the -160A allele was significantly associated with PCA in European Americans (P = 0.04). CONCLUSIONS Our data indicate that CDH1 likely is a low-penetrant PCA susceptibility gene, however, population differences in linkage disequilibrium within the CDH1 gene region may influence the effect of susceptibility alleles such as -160A.
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Affiliation(s)
- Carolina Bonilla
- Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA
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Abstract
Gastric cancer is the second most common cause of cancer death worldwide. It is estimated that 5-10% of gastric cancer cases have a familial association; however, knowledge concerning the genetic predisposition to familial gastric cancer is currently limited. In this chapter we discuss what is known about the aetiology and pathogenesis of both the diffuse and intestinal forms of familial gastric cancer. We focus particularly on hereditary diffuse gastric cancer because the discovery of germ-line E-cadherin mutations in a number of affected families has opened the prospect of identifying gene carriers, with implications for clinical management. The interplay of other conventional risk factors, such as Helicobacter pylori infection, with genetic factors is also discussed. It is hoped that understanding the genetic basis for familial gastric cancer will facilitate the development of clinically useful screening and preventative procedures.
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Affiliation(s)
- Miriam Barber
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK
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Lu Y, Xu YC, Shen J, Yu RB, Niu JY, Guo JT, Hu X, Shen HB. E-cadherin gene C-160A promoter polymorphism and risk of non-cardia gastric cancer in a Chinese population. World J Gastroenterol 2005; 11:56-60. [PMID: 15609397 PMCID: PMC4205384 DOI: 10.3748/wjg.v11.i1.56] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the hypothesis that E-cadherin gene (CDH1) C-160A promoter variant genotype is associated with an increased risk for developing gastric cancer.
METHODS: In this population-based case-control study of gastric cancer in Jiangsu Province, China, we performed polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to genotype the C-160A polymorphism of CDH1 promoter in 206 non-cardia gastric cancer patients and 261 age- and sex-matched but unrelated cancer-free controls.
RESULTS: The frequencies of genotypes CC, CA and AA were 57.8%, 36.4% and 5.8% in gasfric cancer cases, respectively, and 58.2%, 34.9% and 6.9% in controls respectively. The distributions of CDH1 genotypes were not significantly different between gastric cancer cases and controls (P = 0.87 for genotype frequency and P = 0.92 for allele frequency). Compared with the CC genotype, the CA and AA genotypes were not associated with an increased risk for non-cardia gastric cancer (adjusted odds ratios (OR) = 1.15, and 95% confidence interval (95% CI) = 0.78-1.72 for CA genotype, and OR = 0.90 and 95% CI = 0.42-2.01 for AA genotype).
CONCLUSION: E-cadherin gene C-160A promoter polymorphism may not play a major role in the etiology of non-cardia gastric cancer in Chinese population.
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Affiliation(s)
- Yan Lu
- Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, Nanjing 210029, Jiangsu Province, China
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35
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Oliveira C, Suriano G, Ferreira P, Canedo P, Kaurah P, Mateus R, Ferreira A, Ferreira AC, Oliveira MJ, Figueiredo C, Carneiro F, Keller G, Huntsman D, Machado JC, Seruca R. Genetic screening for familial gastric cancer. Hered Cancer Clin Pract 2004; 2:51-64. [PMID: 20233471 PMCID: PMC2839995 DOI: 10.1186/1897-4287-2-2-51] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2004] [Accepted: 05/16/2004] [Indexed: 12/21/2022] Open
Abstract
Approximately 10% of gastric cancer cases show familial clustering but only 1-3% of gastric carcinomas arise as a result of inherited gastric cancer predisposition syndromes. Direct proof that Hereditary Gastric Cancer a genetic disease with a germline gene defect has come from the demonstration of co-segregation of germline E-cadherin (CDH1) mutations with early onset diffuse gastric cancer in families with an autosomal dominant pattern of inheritance (HDGC). E-cadherin is a transmembrane calcium-dependent cell-adhesion molecule involved in cell-junction formation and the maintenance of epithelial integrity. In this review, we describe frequency and type of CDH1 mutations in sporadic and familial gastric cancer. Further we demonstrate the functional significance of some CDH1 germline missense mutations found in HDGC. We also discuss the CDH1 polymorphisms that have been associated to gastric cancer. We report other types of malignancies associated to HDGC, besides diffuse gastric cancer. Moreover, we review the data available on putative alternative candidate genes screened in familial gastric cancer. Finally, we briefly discuss the role of low-penetrance genes and Helicobacter pylori in gastric cancer. This knowledge is a fundamental step towards accurate genetic counselling, in which a highly specialised pre-symptomatic therapeutic intervention should be offered.
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Affiliation(s)
- Carla Oliveira
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.
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Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol 2004; 14:1705-13. [PMID: 14630673 DOI: 10.1093/annonc/mdg486] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Loss of function of the E-cadherin gene (CDH1) has been linked with diffuse gastric cancer susceptibility, and germline inactivating mutations in CDH1 characterise the hereditary diffuse gastric cancer (HDGC) syndrome. Hypermethylation in the CDH1 promoter region is a frequent phenomenon in poorly differentiated, diffuse gastric carcinomas and it was identified as the main mechanism for the inactivation of the remaining wild-type allele in HDGC cases. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers of CDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy. Also, germline CDH1 mutations may predispose to lobular breast carcinoma and prostate cancer. Germline CDH1 mutations are not always detectable in patients who meet the HDGC criteria and the aetiological role of this gene is still under investigation. Families without recognised inactivating CDH1 mutations may have undisclosed CDH1 mutations or mutations in its regulatory sequences or germline mutations in unidentified genes that also contribute to the disease. In recent years, several germline missense CDH1 mutations have been identified, some of which showed a marked negative influence on E-cadherin function in experimental models. CDH1 promoter hypermethylation seems a key event in the carcinogenetic process of poorly differentiated, diffuse gastric cancer and it deserves further investigation as a new target for anticancer therapies with demethylating agents.
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Affiliation(s)
- F Graziano
- Medical Oncology Unit, Hospital of Urbino, Italy.
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Tsukino H, Kuroda Y, Imai H, Nakao H, Qiu D, Komiya Y, Inatomi H, Hamasaki T, Kohshi K, Osada Y, Katoh T. Lack of Evidence for the Association of E-Cadherin Gene Polymorphism with Increased Risk or Progression of Prostate Cancer. Urol Int 2004; 72:203-7. [PMID: 15084762 DOI: 10.1159/000077115] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2003] [Accepted: 08/26/2003] [Indexed: 11/19/2022]
Abstract
BACKGROUND E-cadherin is an epithelial cell adhesion molecule, and decreased E-cadherin expression in human prostate cancer is associated with tumor grade and advanced clinical stage. A -160 C-->A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. MATERIALS AND METHODS We studied the effect of E-cadherin gene polymorphism on prostate cancer susceptibility in a case control study of 219 prostate cancer patients and 219 male controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. RESULTS The genotype frequencies in the prostate cancer group were C/C: 0.607, C/A: 0.352, A/A: 0.041, and in the control group C/C: 0.671, C/A: 0.301, A/A: 0.027. A significant difference between the two groups was not found (p = 0.34), and the adjusted OR for A/A genotype was not statistically significant (OR = 1.66, 95% CI 0.58-4.78). Subdividing prostate cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poor differentiation and invasiveness of prostate cancer. CONCLUSIONS These data do not support an association between the E-cadherin genotype and the occurrence or progression of prostate cancer in Japanese populations.
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Affiliation(s)
- Hiromasa Tsukino
- Department of Public Health, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan
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Shin Y, Kim IJ, Kang HC, Park JH, Park HR, Park HW, Park MA, Lee JS, Yoon KA, Ku JL, Park JG. The E-cadherin -347G->GA promoter polymorphism and its effect on transcriptional regulation. Carcinogenesis 2004; 25:895-9. [PMID: 14729585 DOI: 10.1093/carcin/bgh073] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
E-cadherin plays a critical role in epithelial cell-cell adhesion and maintenance of tissue architecture. Loss of E-cadherin expression in humans has been associated with cancer, and a number of cancer-related mutations have been identified. Here, we sought to investigate whether the -347G-->GA single nucleotide polymorphism affects the transcriptional activity of the E-cadherin gene. First, we measured the promoter activity of the -347G-->GA polymorphism using a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The dual luciferase reporter assay showed that the GA allele decreased the transcriptional efficiency by 10-fold (P < 0.001) compared with the G allele. Similarly, EMSA revealed that the GA allele had a weak transcription factor binding strength compared with the G allele. We then examined the frequency of this polymorphism in familial gastric cancer (FGC) patients by denaturing high-performance liquid chromatography. We found that the E-cadherin genotype (-347G/GA heterozygous or GA homozygous) was associated with FGC patients (P < 0.05) compared with the G homozygous genotype. Taken together, these results suggest that the GA allele may cause weak transcription factor binding affinity and low transcriptional activity in E-cadherin expression.
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Affiliation(s)
- Yong Shin
- Korean Hereditary Tumor Registry, Cancer Research Center and Cancer Research Institute, Seoul National University, South Korea
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40
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Sarrió D, Moreno-Bueno G, Hardisson D, Sánchez-Estévez C, Guo M, Herman JG, Gamallo C, Esteller M, Palacios J. Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer 2003; 106:208-15. [PMID: 12800196 DOI: 10.1002/ijc.11197] [Citation(s) in RCA: 159] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type.
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Affiliation(s)
- David Sarrió
- Laboratory of Breast and Gynecological Cancer, Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
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Tsukino H, Kuroda Y, Nakao H, Imai H, Inatomi H, Kohshi K, Osada Y, Katoh T. E-cadherin gene polymorphism and risk of urothelial cancer. Cancer Lett 2003; 195:53-8. [PMID: 12767511 DOI: 10.1016/s0304-3835(03)00130-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The E-cadherin is important in cell-cell adhesion and in the development and maintenance of the epithelial phenotype. A -160C-->A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation may be a potential genetic marker that can help identify those individuals at higher risk for invasive/metastatic disease. We studied the effect of E-cadherin gene polymorphism on urothelial cancer susceptibility in a case control study of 314 urothelial cancer patients and 314 age-sex matched controls, to determine whether this polymorphism is a biomarker for the risk and how aggressive the disease is. The frequency with which the subjects carried E-cadherin A/A genotype was significantly higher in the urothelial cancer patients than in the healthy control subjects (OR=2.32, 95% CI 1.03-5.22). Subdividing urothelial cancer according to tumor differentiation and stage, we found no association between E-cadherin polymorphism and poorly-differentiation and invasiveness of urothelial cancer. Furthermore, no significant association between E-cadherin polymorphism and recurrence rate of urothelial cancer patients was found. The present study demonstrates for the first time that E-cadherin A/A genotype may be associated with susceptibility to urothelial cancer, but not with the progression of disease.
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Affiliation(s)
- Hiromasa Tsukino
- Department of Public Health, School of Medicine, Miyazaki Medical College, 5200 Kihara, 889-1692 Miyazaki, Japan
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