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

Constitutive activation of the Wnt pathway plays a key role in the development of colorectal cancer and has also been implicated in the pathogenesis of other malignancies. Deregulation of Wnt signaling mainly occurs through genetic alterations of APC, the beta-catenin gene (CTNNB1), AXIN1 and AXIN2, leading to stabilization of beta-catenin. Physiologically, AXIN2 is transcriptionally induced on Wnt signaling activation and acts as a negative feedback regulator of the pathway. In colorectal cancer, mutations in CTNNB1 and AXIN2 occur preferentially in tumors with inactivation of the mismatch repair (MMR) genes MSH2, MLH1, or PMS2. In this study, the expression of beta-catenin and AXIN2, and the mutational status of CTNNB1, APC, and AXIN2 were evaluated in two MMR-deficient (PR-Mel and MR-Mel) and seven MMR-proficient human melanoma cell lines. Only PR-Mel and MR-Mel cells showed nuclear accumulation of beta-catenin and expression of the AXIN2 gene, and hence, constitutive activation of Wnt signaling. Mutational analysis identified a somatic heterozygous missense mutation in CTNNB1 exon three and a germline heterozygous deletion within AXIN2 exon seven in PR-Mel cells, and a somatic biallelic deletion within APC in MR-Mel cells. Deregulation of Wnt signaling and a defective MMR system were also present in the original tumor of PR and MR patients. Thus, we describe additional melanomas with mutations in CTNNB1 and APC, identify for the first time a germline AXIN2 mutation in a melanoma patient and suggest that inactivation of the MMR system and deregulation of the Wnt/beta-catenin signaling pathway cooperate to promote melanoma development and/or progression.
 ...
PMID:Concomitant activation of Wnt pathway and loss of mismatch repair function in human melanoma. 2129 10

The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC (adenomatous polyposis coli), beta-catenin and Axin are frequently mutated in some primary human cancers. This study was conducted to clarify the relation of beta-catenin accumulation and the mutation of the CTNNB1 (beta-catenin) gene with the mutation of APC gene in the process of development of odontogenic tumors including ameloblastoma and odontogenic carcinoma (OC). beta-Catenin accumulation was examined by immunohistochemistry in formalin-fixed, paraffin-embedded samples of six ameloblastomas and eight OCs. We also performed a mutation analysis of CTNNB1 and APC to examine the cause of beta-catenin accumulation. All ameloblastoma cases and six out of eight (75%) OC cases exhibited beta-catenin accumulation in the nucleus. CTNNB1 mutation was only found in one OC case, whereas three of six (50%) ameloblastoma cases and two out of eight (25%) OC cases had APC mutations within the mutational cluster region. Our findings suggest that aberrant beta-catenin expression and APC missense mutation may play an important role for the pathogenesis of epithelial odontogenic tumors.
 ...
PMID:Aberrant beta-catenin expression and adenomatous polyposis coli gene mutation in ameloblastoma and odontogenic carcinoma. 1848 30

Although mutations of APC, CTNNB1 (beta-catenin) and AXIN1 are rare in oral squamous cell carcinoma (OSCC), activation of the Wnt signaling pathway is thought to play an important role in oral carcinogenesis. In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. We frequently detected loss of membrane localization of beta-catenin and its cytoplasmic or nuclear accumulation in OSCC cell lines, although these cell lines showed no APC or CTNNB1 (beta-catenin) mutations and no methylation of CDH1 (E-cadherin). By contrast, we frequently detected methylation of SFRP1 (7/17, 41%) SFRP2 (16/17, 94%) and SFRP5 (14/17, 82%) in a panel of OSCC cell lines, as well as in specimens of primary tumors collected from 44 OSCC patients (SFRP1, 10/42, 24%; SFRP2, 16/44, 36%; SFRP5, 7/43, 16%). We also observed that OSCC cell lines express various Wnt ligands, and that ectopic expression of SFRPs inhibited cancer cell proliferation. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.
 ...
PMID:Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma. 1849 87

We investigated whether one of the Wnt receptors, frizzled-7 (FZD7), functions in the canonical Wnt signaling pathway of colorectal cancer (CRC) cells harboring an APC or CTNNB1 mutation and may be a potential therapeutic target for sporadic CRCs. The expression level of FZD gene family members in colon cancer cells and primary CRC tissues were determined by real-time PCR. Activation of the Wnt signaling pathway was evaluated by TOPflash assay. The expression level of Wnt target genes was determined by real-time polymerase chain reaction and/or Western blot analysis. Cell growth and cell invasion were assessed by MTS and matrigel assays, respectively. Among 10 FZD gene family members, FZD7 mRNA was predominantly expressed in six colon cancer cell lines with APC or CTNNB1 mutation. These six cell lines were transfected with FZD7 cDNA together with a TOPflash reporter plasmid, resulting in a 1.5- to 24.3-fold increase of Tcf transcriptional activity. The mRNA expression levels of seven known Wnt target genes were also increased by 1.5- to 3.4-fold after transfection of FZD7 cDNA into HCT-116 cells. The six cell lines were then cotransfected with FZD7-siRNA and a TOPflash reporter plasmid, which reduced Tcf transcriptional activity to 20% to 80%. FZD7-siRNA was shown to significantly decrease cell viability and in vitro invasion activity after transfection into HCT-116 cells. Our present data demonstrated that FZD7 activates the canonical Wnt pathway in colon cancer cells despite the presence of APC or CTNNB1 mutation and that FZD7-siRNA may be used as a therapeutic reagent for CRCs.
 ...
PMID:Frizzled-7 as a potential therapeutic target in colorectal cancer. 1859 8

Recent studies in mice have shown a role for the canonical WNT pathway in lymphocyte development. Because cancers often arise as a result of aberrant activation of signaling cascades that normally promote the self-renewal and expansion of their progenitor cells, we hypothesized that activation of the WNT pathway might contribute to the pathogenesis of lymphoproliferative disease. Therefore, we screened a large panel (n = 162) of non-Hodgkin lymphomas (NHL), including all major WHO categories, for nuclear expression of beta-catenin, a hallmark of "active" WNT signaling. In 16 lymphomas, mostly of T-lineage origin, nuclear localization of beta-catenin was detected. Interestingly, some of these tumors contained established gain-of-function mutations in the gene encoding beta-catenin (CTNNB1); however, in the majority, mutations in either CTNNB1 or APC were not detected. Functional analysis of WNT signaling in precursor T-lymphoblastic lymphomas/leukemias, the NHL subset in which beta-catenin accumulation was most prevalent (33% positive), revealed a constitutively activated, but still responsive, WNT pathway, which controlled T-cell factor-mediated gene transcription and cell growth. Our data indicate that activation of the WNT pathway, either by CTNNB1 mutation or autocrine stimulation, plays a role in the pathogenesis of a subset of NHLs, in particular, those of T-cell origin.
 ...
PMID:Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies. 1875 11

MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for PTEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis.
 ...
PMID:Endometrial cancer and somatic G>T KRAS transversion in patients with constitutional MUTYH biallelic mutations. 1898 Aug

Sporadic colorectal tumorigenesis is caused by alterations in the Wnt (APC, CTNNB1) and Ras pathways. Our objective was to analyze the occurrence of these genetic alterations in relation to tumor and patient characteristics. The prevalence of somatic alteration in the hot-spot regions of the APC, BRAF, and CTNNB1 genes was investigated in 48 unselected and unrelated Tunisian patients with sporadic colorectal cancer, and the association between the molecular features at these genes in relation to tumor and patient characteristics (age at diagnosis, sex, tumor localization, stage, and differentiation) was analyzed. Loss of heterozygosity was observed at the APC locus in 52% of the analyzed tumors. 6 novel mutations were detected by polymerase chain reaction sequencing in the mutation cluster region of the APC gene. No mutations were observed in the CTNNB1 gene in any tumor, but 8% of tumors harbored mutation in the BRAF gene. Clinicopathological analyses showed an association between APC point mutations and the earliest occurrence of sporadic colorectal cancer. The findings confirm the heterogeneity of APC gene alteration and also reveal a particular profile of this pathology among Tunisian patients that confirms the epidemiological data for this country.
 ...
PMID:Prevalence of mutations in APC, CTNNB1, and BRAF in Tunisian patients with sporadic colorectal cancer. 1899 35

Central nervous system primitive neuroectodermal tumours (CNS PNET) are high-grade, predominantly paediatric, brain tumours. Previously they have been grouped with medulloblastomas owing to their histological similarities. The WNT/beta-catenin pathway has been implicated in many tumour types, including medulloblastoma. On pathway activation beta-catenin (CTNNB1) translocates to the nucleus, where it induces transcription of target genes. It is commonly upregulated in tumours by mutations in the key pathway components APC and CTNNB1. WNT/beta-catenin pathway status was investigated by immunohistochemical analysis of CTNNB1 and the pathway target cyclin D1 (CCND1) in 49 CNS PNETs and 46 medulloblastomas. The mutational status of APC and CTNNB1 (beta-catenin) was investigated in 33 CNS PNETs and 22 medulloblastomas. CTNNB1 nuclear localisation was seen in 36% of CNS PNETs and 27% of medulloblastomas. A significant correlation was found between CTNNB1 nuclear localisation and CCND1 levels. Mutations in CTNNB1 were identified in 4% of CNS PNETs and 20% of medulloblastomas. No mutations were identified in APC. A potential link between the level of nuclear staining and a better prognosis was identified in the CNS PNETs, suggesting that the extent of pathway activation is linked to outcome. The results suggest that the WNT/beta-catenin pathway plays an important role in the pathogenesis of CNS PNETs. However, activation is not caused by mutations in CTNNB1 or APC in the majority of CNS PNET cases.
 ...
PMID:An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumours (CNS PNET). 1929 93

Liver cancers in children are rare representing only 1.1% of malignancies, with an annual incidence rate of 1.5 cases per million. Hepatoblastoma and hepatocellular carcinomas are the most common malignancies of the liver occurring in young people aged 15 years or younger. Molecular basis of both tumors are still unclear, and common markers (i.e., CTNNB1, APC, IGF-2) are not always useful in the characterization of sporadic forms; in this respect, microRNA recently associated with carcinogenesis could play a pivotal role in their onset. CTNNB1 and APC were analyzed by sequencing, and IGF-2 promoter methylation status was assessed by methylation-specific polymerase chain reaction. MicroRNA expression was assayed by microarray and quantitative reverse transcription-polymerase chain reaction in hepatoblastoma samples. Although few genomic alterations were detected in ours samples, an altered expression of somemicroRNA in hepatoblastoma was observed. Unsupervised clustering shows that microRNA profile can distinguish tumor from nontumor tissues. Further analyses of microRNA contents in hepatoblastoma compared with hepatocellular carcinoma highlighted four upregulated microRNA (miR-214, miR-199a, miR-150 [P < .01], and miR-125a [P < .05]) and one downregulated microRNA (miR-148a [P < .01]). In conclusion, although our samples were poorly informative from a genetic point of view, they showed a peculiar microRNA expression pattern compared with nontumor tissues and hepatocellular carcinoma. MicroRNA could represent valid markers for the classification of pediatric liver tumors.
 ...
PMID:Altered microRNA Expression Patterns in Hepatoblastoma Patients. 1970

Aberrant promoter methylation of several known or putative tumor suppressor genes occurs frequently during carcinogenesis, and this epigenetic change has been considered as a potential molecular marker for cancer. We examined the methylation status of nine genes (APC, CDH1, CTNNB1, TIMP3, ESR1, GSTP1, MGMT, THBS1, and TMS1), by quantitative methylation specific PCR. Synchronous preinvasive lesions (atypical ductal hyperplasia and/or ductal carcinoma in situ) and invasive ductal breast carcinoma from 52 patients, together with pure lesions from 24 patients and 12 normal tissues paired to tumor and 20 normal breast distant from tumor were analyzed. Aberrant promoter methylation was detected in both preinvasive and invasive lesions for genes APC, CDH1, CTNNB1, TIMP3, ESR1, and GSTP1. However, hierarchical mixed model and Generalized Estimating Equations model analyses showed that only APC, CDH1, and CTNNB1 promoter regions showed a higher frequency and methylation levels in pathologic samples when compared with normal breast. Whereas APC and CTNNB1 did not show differences in methylation levels or frequencies, CDH1 showed higher methylation levels in invasive tumors as compared with preinvasive lesions (P < 0.04, Mann-Whitney test with permutation correction). The analysis of APC, CDH1, and CTNNB1 methylation status was able to distinguish between normal and pathologic samples with a sensitivity of 67% (95% confidence interval, 60-71%) and a specificity of 75% (95% confidence interval, 69-81%). Our data point to the direct involvement of APC, CDH1, and CTNNB1 promoter methylation in the early stages of breast cancer progression and suggest that they may represent a useful tool for the detection of tumor cells in clinical specimens.
 ...
PMID:Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression. 1978 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>