Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and molecular findings suggest that the four major histological subtypes of ovarian carcinoma (serous, clear cell, mucinous, and endometrioid) likely represent distinct disease entities. Prior studies have shown that ovarian endometrioid adenocarcinomas (OEAs) often carry mutations in the CTNNB1 gene, which encodes beta-catenin, a critical component of the Wnt signaling pathway. However, the nature of other defects in the Wnt signaling pathway in ovarian carcinomas remains largely unknown. Thus, in 45 primary OEAs and two OEA-derived cell lines, we sought to comprehensively address the prevalence of and mechanisms underlying beta-catenin and Wnt pathway deregulation. CTNNB1 missense mutations were detected in 14 primary tumors. All mutations affected the NH(2)-terminal regulatory domain of beta-catenin, presumably rendering the mutant proteins resistant to degradation. Immunohistochemical studies revealed nuclear accumulation of beta-catenin in all but two tumors with CTNNB1 mutations. Two primary tumors lacking CTNNBI mutations showed strong nuclear immunoreactivity for beta-catenin. In one of the two tumors, biallelic inactivation of the APC gene was found. In the remaining 29 primary OEAs, unequivocal nuclear beta-catenin immunoreactivity was not observed, though a nonsense mutation in AXIN1 was observed in one tumor and a truncating frameshift mutation in AXIN2 was seen in another case. Both OEA-derived cell lines studied (TOV-112D and MDAH-2774) had elevated constitutive T-cell factor/lymphoid enhancer factor transcriptional activity. TOV-112D cells were shown to harbor mutant beta-catenin, whereas a missense AXIN1 sequence alteration was identified in MDAH-2774 cells. Collectively, our findings demonstrate frequent defects of the Wnt signaling pathway in a particular subtype of ovarian carcinomas, i.e., OEAs. Although mutations in the CTNNB1 gene are the most common mechanism of beta-catenin deregulation in OEAs, beta-catenin deregulation may also result from mutations in the APC, AXIN1, and AXIN2 genes.
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PMID:Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. 1171 57

The activation of the APC/beta-catenin signalling pathway due to beta-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have beta-catenin nuclear accumulation without evidence of beta-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, gamma-catenin, AXIN1 and AXIN2. We investigated the expression pattern of beta- and gamma-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, beta- and gamma-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear beta-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with beta-catenin gene exon 3 mutations (P<0.0001). beta-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). gamma-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in gamma-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with beta-catenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/beta-catenin pathway, but only mutations in beta-catenin gene are associated with aberrant nuclear localization of beta-catenin.
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PMID:Abnormalities of the APC/beta-catenin pathway in endometrial cancer. 1243 48

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS-regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch-repair-deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite-unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch-repair-deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild-type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch-repair-deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation.
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PMID:Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. 1469 93

Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.
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PMID:Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. 1505 82

Aberrant Wnt signaling, mainly through mutations of APC and in some cases of CTNNB1 or AXIN2, has been found in the majority of colorectal cancers. Recently, frequent promoter hypermethylation was identified to cause silencing of the secreted frizzled-related protein (sFRP) family in colorectal cancer. Restoration of sFRP in colorectal cancer cells attenuates Wnt signaling even in the presence of downstream mutations. Here we show that Wnt inhibitory factor-1 (WIF-1), a different secreted antagonist of Wnt signaling, is also silenced by promoter hypermethylation in colorectal cancer cells. Restoration of WIF-1 function, Wnt-1 siRNA, or a monoclonal anti-Wnt-1 antibody that we developed attenuates Wnt-1 signaling and induces significant apoptosis in these cells containing downstream mutations and expressing Wnt-1. In addition, this monoclonal anti-Wnt-1 antibody showed synergistic effects with docetaxel in treating these colorectal cancer cells and great efficacy in treating primary colorectal cancer cultures freshly prepared from patients. Therefore, our data support the hypothesis that constitutive Wnt signaling may be required to complement downstream mutations in the evolution of colorectal cancer. Furthermore, our results suggest that blockade of the Wnt signal may have a therapeutic role in the treatment of colorectal cancer.
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PMID:Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. 1573 84

An unselected series of 310 colorectal carcinomas, stratified according to microsatellite instability (MSI) and DNA ploidy, was examined for mutations and/or promoter hypermethylation of five components of the WNT signaling cascade [APC, CTNNB1 (encoding beta-catenin), AXIN2, TCF4, and WISP3] and three genes indirectly affecting this pathway [CDH1 (encoding E-cadherin), PTEN, and TP53]. APC and TP53 mutations were each present more often in microsatellite-stable (MSS) tumors than in those with MSI (P < .001 for both). We confirmed that the aneuploid MSS tumors frequently contained TP53 mutations (P < .001), whereas tumors with APC mutations and/or promoter hypermethylation revealed no associations to ploidy. Mutations in APC upstream of codons 1020 to 1169, encoding the beta-catenin binding site, were found in 15/144 mutated tumors and these patients seemed to have poor clinical outcome (P = .096). Frameshift mutations in AXIN2, PTEN, TCF4, and WISP3 were found in 20%, 17%, 46%, and 28% of the MSI tumors, respectively. More than half of the tumors with heterozygote mutations in AXIN2 were concurrently mutated in APC. The present study showed that more than 90% of all samples had alteration in one or more of the genes investigated, adding further evidence to the vital importance of activated WNT signaling in colorectal carcinogenesis.
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PMID:Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. 1580 15

Mutations in APC, CTNNB1, AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers. Accumulated beta-catenin then associates with Tcf/LEF transcription factors and transactivates their target genes. To uncover in detail the role of accumulated beta-catenin in colorectal carcinogenesis, we searched for genes involved in the beta-catenin/Tcf signaling pathway by cDNA microarray. We identified and characterized a human gene, SP5, that was down-regulated after depletion of beta-catenin by transduction of wild-type APC into SW480 cells. SP5 is a member of the Sp transcription factor family, which binds to the GC box or closely related sequences in promoters of many genes and control their expression. Reporter assays and an electromobility-shift assay revealed a DNA fragment between -285 and -279 in the 5' flanking region of this gene to be a target of the beta-catenin/Tcf4 complex. Our results indicate that SP5 is a novel direct down-stream target in the Wnt signaling pathway.
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PMID:Identification of SP5 as a downstream gene of the beta-catenin/Tcf pathway and its enhanced expression in human colon cancer. 1627 2

Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here we demonstrate that Wnt/beta-catenin signaling causes CIN via up-regulation of conductin. Human colon tumor samples with CIN show significantly higher expression of conductin than those without. Conductin is up-regulated during mitosis, localizes along the mitotic spindles of colon cancer cells, and binds to polo-like kinase 1. Ectopic expression of conductin or its up-regulation through small interfering RNA-mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells. High conductin expression compromises the spindle checkpoint, and this requires localized polo-like kinase 1 activity. Knock-down of conductin by small interfering RNA in colon carcinoma cells or gene ablation in mouse embryo fibroblasts enforces the checkpoint.
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PMID:Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer. 1681 67

Alterations in the cadherin-catenin expression and activation of the Wnt signaling have been related to the pathology of ovarian carcinomas. Here, we evaluated the immunoreactivity of cadherins (E-, P-, and N-cadherin and cadherin-11) and catenins (alpha-, beta-, and gamma-catenin and p120) in 86 ovarian tumors. We found significant differences in the expression of all cadherins and catenins among the distinct histologic tumor types. Clear cell tumors were rarely N-cadherin- and P-cadherin-positive and showed reduced membranous expression in all the catenins; Serous carcinomas were frequently N-cadherin- and P-cadherin-positive, mucinous tumors strongly expressed E-cadherin and the catenins in the membrane, and endometrioid tumors characteristically expressed nucleocytoplasmic beta-catenin in most of the cases. We next studied whether allelic losses in the chromosomal regions containing various cadherin genes (16q22) or APC gene (5q21) occurred in ovarian tumors and observed a high frequency of loss of heterozygosity in 16q22 (78%) and 5q21 (33%) regions, but there were no differences among the tumor types analyzed. Finally, we also assessed the molecular alterations responsible for beta-catenin nuclear accumulation in endometrioid tumors by screening for mutations in AXIN1, AXIN2, APC, and KRAS genes. Mutations in KRAS were observed in 2 of 19 tumors, but no mutations were detected in AXIN1, AXIN2, or APC genes. Only beta-catenin gene mutations were associated with nuclear beta-catenin staining in these tumors. In conclusion, different cadherin-catenin expression patterns are associated with distinct histologic types. Oncogenic Wnt signaling plays a role only in endometrioid tumors, where beta-catenin mutations seem to be the main cause of its aberrant expression.
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PMID:Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas. 1686 67

Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance.
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PMID:Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. 1694 1


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