Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular basis for most non-HNPCC familial colorectal cancer cases is unknown, but there is increasing evidence that common genetic variants may play a role. We investigated the contribution of polymorphisms in two genes implicated in the pathogenesis of colorectal cancer, cyclin D1 (CCND1) and E-cadherin (CDH1), to familial and sporadic forms of the disease. The CCND1 870A/G polymorphism is thought to affect the expression of CCND1 through mRNA splicing and has been reported to modify the penetrance of HNPCC. Inactivation of E-cadherin is common in colorectal cancer, and truncating germline mutations have been reported to confer susceptibility to colorectal as well as diffuse gastric cancer. The -160A/C CDH1 polymorphism appears to affect expression of CDH1 and may therefore also confer an increased risk. We found a significantly higher frequency of CCND1 870A allele in 206 familial cases compared to 171 controls (P=0.03). Odds ratios in heterozygotes and homozygotes were 1.7 (95% CI: 1.0-2.66) and 1.8 (95% CI: 1.0-3.3) respectively. The difference was accounted for by an over-representation of A allele in non-HNPCC familial cases (P=0.007). Over-representation of the CCND1 A allele was also seen in sporadic colorectal cancer cases compared to controls but this did not attain statistical significance (P=0.08). No significant differences between the frequency of CDH1 -160A/C genotypes in familial, sporadic colorectal cancer cases and controls were seen, although a possible association between the low expressing A allele and right-sided tumours was detected in familial cases.
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PMID:Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. 1189 26

Somatic mutations in the E-cadherin (CDH1) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with hereditary prostate cancer (HPC), a significant association of prostate cancer, gastric and/or breast cancer has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in CDH1 could explain the risk for cancer in HPC families with an excess of gastric and breast cancer. In total, 17 members from 13 HPC families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline CDH1 sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with hereditary prostate cancer and 215 cases of sporadic prostate cancer with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the HPC families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687+92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687+92T>A were found in the extended HPC material or in the sporadic prostate cancer cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the CDH1 gene that probably do not explain the association of prostate, gastric and/or breast cancers in the HPC-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of hereditary or sporadic prostate cancer in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family.
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PMID:Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. 1194 60

The International Gastric Cancer Linkage Consortium (IGCLC) predicted that up to 25% of families fulfilling the criteria for hereditary diffuse gastric cancer (HDGC) would harbor CDH1 germline mutations. This was based on observations from the low number of diffuse gastric cancer families described at the time, and its validation would require analysis of larger numbers. Here we report the results of germline CDH1 mutation screening in 39 kindred with familial aggregation of gastric cancer, a subset of which fulfills the criteria defined by the IGCLC for HDGC. CDH1 germline mutations were detected in four of 11 (36.4%) HDGC families. No mutations were identified in 63.6% of HDGC families or in kindred with familial aggregation of gastric cancer not fulfilling criteria for HDGC. These results add support to the evidence that only HDGC families harbor germline mutations in CDH1 and that genes other than CDH1 remain to be identified.
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PMID:Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. 1196 83

Hereditary diffuse gastric cancer (HDGC) is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the gene for the cell-to-cell adhesion protein E-cadherin (CDH1). Here, we describe the search for CDH1 mutations in 10 newly identified gastric cancer families. Seven of 10 families met the clinical criteria for HDGC. Germline mutations were identified in four of these seven families and one family that was borderline for the clinical criteria. Of the mutations identified in the five new families, four were previously unreported and consisted of two frameshift and two donor splice site mutations. One splice site mutation occurred at the 100% conserved +1 position. The second splice site mutation occurred at the +5 position and was shown to lead to abnormal splicing. Additional CDH1 variants detected include the heterozygous -160 C-->A promoter polymorphism, which has previously been reported to be associated with decreased CDH1 transcription. We, however, found this polymorphism to be common in a control population, suggesting that a major role for this polymorphism in gastric cancer susceptibility is unlikely.
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PMID:Novel germline CDH1 mutations in hereditary diffuse gastric cancer families. 1196 84

Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons. The majority of gastric tumors are sporadic in nature. However, there are rare, inherited gastric cancer predisposition traits, such as germline p53 (Li-Fraumeni syndrome) as well as E-cadherin (CDH1) alterations in familial diffuse gastric cancers. Gastric cancer has been observed to be part of the spectrum of neoplasms associated with germline mismatch repair gene (MMR) alterations that give rise to the hereditary nonpolyposis colorectal cancer (HNPCC) entity. Comparative genomic hybridization analyses have identified several amplifications and losses of DNA copy numbers in gastric cancers. Loss of heterozygosity (LOH) studies have shown several chromosomal loci with significant allelic loss, thus indicating the possibility of harboring a tumor suppressor gene important in gastric tumorigenesis. Microsatellite instability (MIS) and associated alteration of the TGF-bIIR, IGFRII, BAX, E2F-4, hMSH3, and hMSH6 genes are found in a subset of gastric carcinomas. Cell adhesion molecule abnormalities such as those involving CDH1 may play an important role in diffuse-type gastric cancer development. Although, multiple somatic alterations have been described in gastric carcinomas at the molecular level, the significance of these changes in gastric tumorigenesis remains to be established in most instances. The critical molecular alterations in gastric cancers that may lead to advances in our armamentarium to combat this lethal disease remain to be fully characterized.
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PMID:Molecular biology of gastric cancer. 1197 14

We have combined data from case control studies designed to test the hypothesis that the c-160a promotor polymorphism in the gene coding for the cell adhesion molecule E-cadherin (CDH1) is associated with stomach cancer. A total of 899 individuals (433 patients and 466 controls) were analyzed. The genotype frequencies did not differ significantly between cases and controls, and the genotype-specific risks were not significantly different from unity, with an odds ratio for heterozygotes compared with the common homozygote of 1.3 (95% CI 0.98-1.8) and 1.2 (0.68-2.0) for rare homozygotes compared with common homozygotes. We found no evidence for differences in risk for the intestinal- and diffuse-type histopathologic subgroups.
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PMID:CDH1 c-160a promotor polymorphism is not associated with risk of stomach cancer. 1220 98

Truncating mutations in the gene for the cell to cell adhesion protein E-cadherin are the most consistent genetic alterations observed in sporadic and hereditary diffuse gastric cancer (DGC). In addition to these inactivating mutations, a CDH1 promoter polymorphism at position -160 has been reported to lead to transcriptional downregulation of the gene in vitro. We therefore performed a case-control study to investigate whether this variant is associated with an increased susceptibility to DGC. The frequency of the -160A allele was significantly higher (P<0.005) in 53 diffuse gastric cancer cases compared to 70 matched controls. The odds ratio associated with the A-allele was 2.27 for CA-heterozygotes (95%CI 1.16-4.44) and 7.84 for AA-homozygotes (95%CI 2.89-21.24). Two additional polymorphisms (the 48+6T-->C and the 2076C-->T variant) were genotyped and shown to be equally distributed among cases and controls. Haplotype analysis with the three polymorphisms confirmed an association with disease (P<0.004). However, this analysis suggested the -160C-->A CDH1 promoter polymorphism may be in linkage disequilibrium with a distinct aetiological locus or acts in combination with other functional variants in or near the CDH1 region.
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PMID:Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer. 1244 56

Human SNAIL1 (SNAI1) protein encoded by SNAI1/SNA gene represses transcription of E-cadherin/CDH1 gene. Human SNAIL2 (SNAI2) protein encoded by SNAI2/SLUG gene induces the first phase of epithelial-mesenchymal transition (EMT), including desmosome dissociation, cell spreading, and initiation of cell separation. Here, we have identified human SNAIL3 (SNAI3) gene using bioinformatics. Human SNAI3 gene, consisting of at least three exons, spans around the nucleotide position 320214-328221 of human reference genomic contig NT_010404.8 in the reverse orientation. SNAI3 gene, was located between KIAA0233 gene and CBFA2T3 gene in human chromosome 16q24.3, a region affected in breast cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, and therapy-related myeloid leukemia with t(16;21)(q24;q22) translocation. Human SNAI3 gene was found to encode 292-amino-acid polypeptide with the N-terminal SNAG domain and five zinc finger domains. N-terminal SNAG domain was identified in zinc finger proteins SNAI1, SNAI2, SNAI3, SCRATCH (SCRT1), GFI1, and GFI1B. ATP/GTP binding site was identified in SCRT1, GFI1 and GFI1B, but not in SNAI1, SNAI2 and SNAI3. Phylogenetic analysis of human zinc finger proteins with SNAG domain revealed that SNAI1, SNAI2 and SNAI3 were more closely related. These results clearly indicate that SNAI1, SNAI2 and SNAI3 constitute a subfamily among SNAG zinc-finger proteins. Human SNAI3 mRNA was expressed in skin melanotic melanoma, lung epidermoid carcinoma, and germ cell tumor. Because SNAG zinc-finger proteins are transcriptional repressors implicated in carcinogenesis and embryogenesis, SNAI3 gene might be a potent target of pharmacogenomics in the field of oncology and regenerative medicine.
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PMID:Identification and characterization of human SNAIL3 (SNAI3) gene in silico. 1257 45

E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.
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PMID:Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. 1258 4

The origin, characteristics, and lifetime risk for the following five types of hereditary cancer (HCS) syndromes are briefly described in this review: hereditary breast and ovarian cancer (HBOC) syndrome, familial adenomatous polyposis (FAP), and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, hereditary diffuse gastric cancer (HDGC) syndrome, and medullary thyroid carcinoma (MTC). Most are caused by mutations in tumor suppressor genes. In HCS, a single copy of the mutated tumor suppressor gene is inherited, and mutation of the second wild type allele of the gene is required for tumorigenesis. Patients with HCS have a higher than normal risk of a second malignancy. Management strategies to address increased cancer risk in HCS include genetic counseling and testing, targeted surveillance, chemoprevention, and prophylactic surgery. Genetic testing for high-risk family members is strongly recommended. Available data indicate surgical prophylaxis is more successful than surveillance in reducing cancer risk in carriers of BRCA, CDH1, APC, and RET mutation.
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PMID:Molecular genetics and management strategies in hereditary cancer syndromes. 1267 1


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