Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The type II transforming growth factor (TGF)-beta receptor gene (TGFBR2) is often mutated in nucleotide repeat sequences in colorectal cancers that are replication error positive (RER+). These mutations are thought to be selected for escape from growth inhibition by TGF-beta rather than representing bystander events because of an increased mutation rate. We investigated the role of TGFBR2 mutations in 12 colorectal cancer cell lines. Six of these were RER+, and these were shown to have homozygous TGFBR2 mutations. All cell lines then were tested for changes in proliferation in response to TGF-beta stimulation. Despite homozygous mutation of the type II TGF-beta receptor, two RER+ cell lines, Lovo and SW48, showed statistically significant growth inhibition when stimulated by TGF-beta1 in serum-free conditions. This shows that the type II TGF-beta receptor can be bypassed in certain cases to maintain growth inhibition. We next investigated whether there was any alternative mode through which TGFBR2 mutation may give a selective advantage, such as a change in adhesion molecule expression. All cell lines were stimulated with TGF-beta1 and adhesion molecules detected by ELISA. No consistent changes were identified between the RER+ and the RER- cell lines, although changes in E-cadherin, beta-catenin, and gamma-catenin were identified in individual cell lines. We conclude that (i) type II TGF-beta receptor activity can be bypassed and thus TGFBR2 mutations in RER+ cancers may, at least sometimes, be just "bystander" events and (ii) TGF-beta can affect adhesion molecule expression so that TGFBR2 mutation may give rise to a selective advantage through an effect other escape from growth inhibition.
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PMID:Transforming growth factor beta stimulation of colorectal cancer cell lines: type II receptor bypass and changes in adhesion molecule expression. 1007 41

The tumor-suppressor protein Dpc4 (Smad4, Madh4) regulates gene expression. On binding of an extracellular ligand of the extensive transforming growth factor (TGF) superfamily to its cognate receptor complex, latent cytoplasmic Dpc4 is activated and translocated into the nucleus to function as part of various DNA-binding transcriptional activator complexes. The most relevant ligand/receptor pair to control the tumor suppressive function of Dpc4 remains uncertain, but is usually assumed to be TGF-beta and its heteromeric receptor. We exploited a fortuitous experiment of nature to directly test this hypothesis: the TGF-beta type II receptor gene is inactivated by mutation in nearly all colorectal carcinomas having microsatellite instability, as seen in hereditary nonpolyposis colorectal cancer (HNPCC) and in sporadic medullary colorectal cancers. Using a specific and sensitive immunohistochemical label for Dpc4, we examined nuclear localization of Dpc4 in 13 HNPCC, six medullary, and 41 sporadic nonmedullary colorectal carcinomas. In agreement with published rates, two (5%) of 41 sporadic tumors showed complete loss of Dpc4 protein, indicative of genetic inactivation. All 13 HNPCC and six medullary tumors had intact cytoplasmic and nuclear Dpc4 localization. The TGFBR2 gene was sequenced in three of the cancers from patients with HNPCC, and all of these harbored inactivating mutations. The specificity of the immunohistochemical assay was demonstrated in xenograft tumors of syngeneic cell lines that differed in DPC4 genetic status because of an engineered gene knockout. Thus, nuclear localization of Dpc4 can be maintained in cells with inactivated TGF-beta type II receptors, suggesting the persistence of tumor-suppressive action of an upstream signaling input, most likely a ligand/receptor complex distinct from TGF-beta. Identification of the relevant input would be expected to have implications for the understanding of tumorigenesis and the design of rational biological therapy.
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PMID:Nuclear localization of Dpc4 (Madh4, Smad4) in colorectal carcinomas and relation to mismatch repair/transforming growth factor-beta receptor defects. 1115 90

Colorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. Colorectal cancer develops as the result of the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma. The loss of genomic stability is a key molecular and pathophysiologic step in this process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. Alterations in these genes, which include APC, CTNNB1, K-RAS, MADH4/SMAD4, and TGFBR2, appear to promote colon tumorigenesis by perturbing the function of signaling pathways, such as the TGF-ss signaling pathway, or by affecting genes that regulate genomic stability, such as the mutation mismatch repair genes.
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PMID:Genetic and epigenetic alterations in colon cancer. 1214 55

Colorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. At the cellular level, colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelial cells to colon adenocarcinoma cells. The loss of genomic stability appears to be a key molecular and pathogenetic step that occurs early in the tumorigenesis process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. At least three forms of genomic instability have been identified in colon cancer: (1) microsatellite instability (MSI), (2) chromosome instability (i.e. aneusomy, gains and losses of chromosomal regions) (CIN), and (3) chromosomal translocations. Microsatellite instability occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. CIN appears to result primarily from deregulation of the DNA replication checkpoints and mitotic-spindle checkpoints. The mechanisms that induce and influence genomic instability in cancer in general and more specifically in colon cancer are only partly understood and are consequently under intense investigation. These studies have revealed mutation of the mitotic checkpoint regulators BUB1 and BUBR1 and amplification of STK15 in a subset of CIN colon cancers. The etiology of CIN in the other unexplained cases of colon cancer remains to be determined. Hopefully, discovery of the cause and specific role of genomic instability in colon cancer will yield more effective chemotherapy strategies that take advantage of this unique characteristic of cancer cells.
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PMID:Genomic instability and colon cancer. 1500 Jan 46

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal inherited cancer syndrome characterized by germline plus somatic mutations of DNA mismatch repair genes and familial clustering of cancers of colorectum and other visceral organs. So far, to our knowledge, there has been no proof of nonepithelial tumors in association with HNPCC. Here we report on a MSH2 frameshift HNPCC family with a carrier found to have multiple primary tumors, including endometrial hyperplasia, ovarian adenocarcinoma, skin cavernous hemangioma, and skin dermatofibrosarcoma protuberans (DFSP). We studied the replication error (RER) phenotype in noncoding (Bat-26, Bat-25, D2S123, D5S346, and D17S250) and coding (MSH3, MSH6, BAX, and TGFBR2 genes) DNA sequences, and characterized the germline and somatic mutations of the MSH2 gene in the tumors described above and in endometrial carcinomas from two of her affected siblings. RER was observed in an order of hyperplasic endometrium (6/10 markers), ovarian carcinoma (5/10 markers), endometrial carcinomas (4/9 and 3/10), DFSP (2/9 markers), and cavernous hemangioma (2/10 markers). All the tumors showed the same germline mutation of G5-->G6 frameshift at 183-187 and polymorphism of C1168T in a heterozygous pattern. In an endometrial carcinoma, deletion of the second allele of MSH2 was evident. Heterogeneous RER patterns were noted in multiple primary tumors of the same individual and in premalignant and malignant endometrial tumors from different individuals. The study demonstrated the two hits of the hMSH(2) gene as well as intra- and interindividual variations of RER phenotypes in HNPCC. The first characterized nonepithelial tumors in HNPCC seem to carry a limited panel of RER, including a framesift at the (A)(10) tract of TGFBR2.
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PMID:Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes. 1535 Feb 99

The mutator pathway implied in the development of colorectal cancer is characterized by microsatellite instability (MSI), which is determined by alterations of mismatch repair (MMR) genes. Defects in MMR genes affect repetitive DNA tracts interspersed mostly between coding sequences, and therefore it cannot be expected that they play a role during tumor progression. Genes containing repetitive sequences within their coding regions could be targets for MSI tumorigenesis, but this does not necessarily imply a causal role for the affected gene, because most are probably passenger mutations. We analyzed MSI and TGFBR2 and BAX frameshift mutations to further clarify the relationships between inactivation of the two genes and genomic instability in sporadic colorectal cancer (CRC), and to address how mutations in these genes influence the development of tumors and, eventually, patient outcome. One hundred and fifty-five patients with sporadic CRC were classified according to their MSI status. Frameshift mutations in the two genes were recurrent in high-frequency MSI (MSI-H) tumors, but these tended to be more common in poorly differentiated tumors. A high rate of mutations of TGFBR2 was found in tumors at Dukes' B stage, showing a greater extent of vascular invasion. Finally, in MSI-H tumors, mutations of either gene were associated with a significant decrease in survival. Our results contribute to the understanding of how the TGFBR2 and BAX gene mutations contribute to tumor progression in the mutator phenotype pathway for MSI colorectal cancers.
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PMID:Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability. 1567 42

Tumorigenesis is a multistep process characterized by a myriad of genetic and epigenetic alterations. Identifying the causal perturbations that confer malignant transformation is a central goal in cancer biology. Here we report an RNAi-based genetic screen for genes that suppress transformation of human mammary epithelial cells. We identified genes previously implicated in proliferative control and epithelial cell function including two established tumor suppressors, TGFBR2 and PTEN. In addition, we uncovered a previously unrecognized tumor suppressor role for REST/NRSF, a transcriptional repressor of neuronal gene expression. Array-CGH analysis identified REST as a frequent target of deletion in colorectal cancer. Furthermore, we detect a frameshift mutation of the REST gene in colorectal cancer cells that encodes a dominantly acting truncation capable of transforming epithelial cells. Cells lacking REST exhibit increased PI(3)K signaling and are dependent upon this pathway for their transformed phenotype. These results implicate REST as a human tumor suppressor and provide a novel approach to identifying candidate genes that suppress the development of human cancer.
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PMID:A genetic screen for candidate tumor suppressors identifies REST. 1596 Sep 67

Microsatellite instability (MSI) due to mismatch repair system (MMR) alterations characterizes the mutator pathway implied in colorectal cancer development. In the present study, we have analyzed the gene RIS1 (Ras-induced senescence 1) in relation to loss of heterozygosity (LOH) and its frameshift mutations for an imperfect trinucleotide repeat (GCN) located at the 3'-OH end. Additionally, we have compared the status of RIS1 with a number of genetic and clinicopathological variables. RIS1 did not display LOH in any informative tumor of our series, but exhibited frameshift mutations in a high percentage (43.8%) of high-frequency MSI tumors (MSI-H), and its alteration was correlated with mutations in two target genes: BAX and TGFBR2. Moreover, mutations in RIS1 in MSI-H tumors correlated with the epigenetic silencing of MLH1 (P = 0.04). Finally, RIS1 seemed to be functionally involved in tumor development, as low-frequency MSI tumors (MSI-L) with RIS1 mutated usually were associated with a worse prognosis: 83% of them developed metastasis, and no patient with MSI-L tumor and RIS1 mutated (35.3% of MSI-L) survived >25 months after surgery (log rank P < 0.001). All these results indicate, according to the Bethesda criteria, that RIS1 is a target gene in the mutator pathway.
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PMID:RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis. 1673 13

Insulin-like growth factor binding protein 3 (IGFBP3), which is induced by wild-type p53, regulates IGF and interacts with the TGF-beta pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight), we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1). IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41) than in MSI-high CIMP-high (49% = 44/90, P < .0001), MSI-high non-CIMP-high (17% = 6/36, P < .0001), and non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001). Among CIMP-high tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001), but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02). In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, and this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/CIMP), single molecular events (e.g., IGFBP3 methylation, TP53 mutation, and TGFBR2 mutation), and the related pathways.
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PMID:IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53. 1808 16

Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3+ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.
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PMID:Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. 1950 63


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