Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial (E)-cadherin and its associated cytoplasmic proteins (alpha-, beta-, and gamma-catenins) are important mediators of epithelial cell-cell adhesion and intracellular signaling. Much evidence exists suggesting a tumor/invasion suppressor role for E-cadherin, and loss of expression, as well as mutations, has been described in a number of epithelial cancers. To investigate whether E-cadherin gene (CDH1) mutations occur in colorectal cancer, we screened 49 human colon carcinoma cell lines from 43 patients by single-strand conformation polymorphism (SSCP) analysis and direct sequencing. In addition to silent changes, polymorphisms, and intronic variants in a number of the cell lines, we detected frameshift single-base deletions in repeat regions of exon 3 (codons 120 and 126) causing premature truncations at codon 216 in four replication-error-positive (RER+) cell lines (LS174T, HCT116, GP2d, and GP5d) derived from 3 patients. In LS174T such a mutation inevitably contributes to its lack of E-cadherin protein expression and function. Transfection of full-length E-cadherin cDNA into LS174T cells enhanced intercellular adhesion, induced differentiation, retarded proliferation, inhibited tumorigenicity, and restored responsiveness to the migratory effects induced by the motogenic trefoil factor 2 (human spasmolytic polypeptide). These results indicate that, although inactivating E-cadherin mutations occur relatively infrequently in colorectal cancer cell lines overall (3/43 = 7%), they are more common in cells with an RER+ phenotype (3/10 = 30%) and may contribute to the dysfunction of the E-cadherin-catenin-mediated adhesion/signaling system commonly seen in these tumors. These results also indicate that normal E-cadherin-mediated cell adhesion can restore the ability of colonic tumor cells to respond to trefoil factor 2.
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PMID:Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells. 1005 39

Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.
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PMID:Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. 1007 28

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

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

E-cadherin belongs to the cadherin family of calcium-dependent cell-adhesion molecules. The cadherins play an essential role in biological processes such as ordering of cell sorting, migration, and differentiation, and their malfunctioning is connected with neoplasia. Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia. Transcriptional silencing of tumor-suppressor genes by promoter methylation has been observed in different types of human cancers and dysplasia. To explore the mode of E-cadherin regulation, 156 biopsy samples from 26 patients with long-standing ulcerative colitis were screened. To detect the methylation status of our samples, a methylation-specific PCR was applied. Methylation of the E-cadherin (CDH1) promoter was detected in 93% of the patients with dysplastic biopsy samples, in contrast to only 6% of the patients without dysplasia (P < 0.001). We also examined the level of synthesis of E-cadherin protein by immunohistochemical staining in different paraffin-embedded samples of dysplastic and non-dysplastic origin in a subset of our patients. Samples with dysplasia displayed reduced levels, whereas samples without dysplasia revealed normal E-cadherin protein synthesis. These results show that the E-cadherin promoter is subjected to epigenetic control in colorectal ulceration. Obviously, this event may play an important role in the progression from chronic inflammation to colorectal cancer. For this reason, methylation of the CDH1 promoter is an attractive new biomarker for detecting ulcerative colitis patients with a high risk for developing colorectal cancers.
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PMID:Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. 1220 75

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

E-cadherin (CDH1) gene expression is strictly regulated. The transcriptional factors SNAIL and ZEB1 are involved in its repression, whereas activation of vitamin D receptor (VDR) by vitamin D induces its transcription. We study the expression and functional correlation of SNAIL, CDH1, VDR and ZEB1 genes and examine their possible involvement in colon cancer. The expression of these four genes was measured by real time-PCR in 114 patients with colorectal cancer, and tumor characteristics were analyzed in each patient. SNAIL expression was associated with downregulation of CDH1 (P < 0.001) and VDR (P < 0.001) gene products. We also found a positive correlation between CDH1 and VDR expressions. However, the association between SNAIL and CDH1 was not found in patients with high expression of ZEB1. We observed a correlation between downregulation of: a) ZEB1 and presence of polyps in surgical resections; b) VDR and poor differentiation and c) CDH1 and poor differentiation, vascular invasion, presence of lymph node metastases and advanced stages; as well as a trend toward a correlation between SNAIL expression in tumors and vascular invasion. The correlations between SNAIL, CDH1, VDR and ZEB1 and the association between reduced expression of CDH1 and VDR and aggressive tumor characteristics emphasize the value of analyzing these genes in colon cancer patients for prognostic purposes and for predicting response to possible therapies with vitamin D or its analogs.
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PMID:E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. 1620 44

Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of the gene encoding the tumour-suppressor E-cadherin (CDH1). We describe the search for CDH1 mutations in 36 new diffuse gastric cancer families. All 16 CDH1 exons, neighbouring intronic sequence and an essential promoter region were screened by DNA sequencing. We detected nine different mutations, seven of which were novel. Of the seven novel mutations, five were identified in families who met the IGCLC clinical criteria for HDGC. Two mutations resulted in a premature stop codon and truncation of the protein. Three mutations affected splice sites; two of the splice-site mutations were shown by RT-PCR to disturb normal CDH1 splicing, while the third splice-site mutation was present in two unrelated HDGC families. The remaining two mutations resulted in amino acid substitutions and impaired the ability of E-cadherin protein to form cellular aggregates and suppress invasion in vitro. Together with the occurrence of extra-gastric tumours such as lobular breast and colorectal cancer, these findings further extend the types of CDH1 mutations and the spectrum of tumours associated with HDGC.
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PMID:Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene. 1722 70

Colorectal cancer (CRC) with liver metastasis is a fatal disease with rapid progression and poor patient outcome. However, the molecular mechanism involved in liver metastasis of CRC remains essentially unknown, largely because of the presence of few available CRC cell lines with liver metastasis origin and spontaneous metastatic potentials in nude mice. In this study, we established a novel metastatic CRC cell line, CLY, derived from liver metastasis of a 64-year-old Chinese CRC patient. The cell line was characterized by morphology, growth kinetics, tumorigenicity, spontaneous liver metastatic potential, and cytogenetics. Immunofluorescence analysis of beta-catenin and E-cadherin and methylation-specific PCR (MSP) of the E-cadherin gene (CDH1) promoter were also used to compare CLY with conventional CRC cell lines (HT-29 and Lovo). CLY exhibited compact and polygonal-shaped epithelial cells in vitro and its population doubling time was 29.5 h. Subcutaneous transplantation of CLY into nude mice resulted in subcutaneous tumor formation and spontaneous liver metastasis in all of 10 nude mice. Cytogenetic analysis identified aneuploidy karyotypes with a modal chromosome number of 60. In immunofluorescence analysis, CLY exhibited a low expression but high restricted nuclear localization of beta-catenin and a silenced expression of E-cadherin, which may be induced by hypermethylation of the E-cadherin gene (CDH1) promoter and differed from conventional CRC cell lines. Therefore, CLY is an ideal cell model for further exploring the metastatic mechanisms of CRC and testing new therapeutic reagents for CRC with liver metastasis.
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PMID:Establishment and characterization of a novel human colorectal cancer cell line (CLY) metastasizing spontaneously to the liver in nude mice. 1734 24

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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PMID: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. 1819 81


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