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)

Recent studies have mapped two susceptibility loci which appear to account for familial multinodular goitre (MNG1) and a variant of familial papillary thyroid cancer (PTC), with associated multinodular goitre (TCO). A Tasmanian family (Tas1) has been identified with an autosomal dominant form of PTC. This study has examined the MNG1 and TCO loci to determine if they are similarly predisposing the Tas1 family to PTC. Linkage analysis using identical microsatellite markers described in the two previous studies was used to determine the significance of these loci in the Tasmanian family. The resultant LOD scores were sufficiently negative using multipoint parametric analysis to exclude these two loci from involvement in the Tasmanian family. In addition, six candidate genes, RET, TRK, MET, TSHR, APC and PTEN were also excluded as susceptibility genes in Tas1 by using microsatellites that are positioned in or in close proximity to these genes. These results suggest that there are at least three susceptibility genes that predispose families to familial PTC.
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PMID:At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family. 1042 54

Relative peak-height ratios of products to substrates determined by MALDI-TOFMS allow the quantitative analysis of enzyme catalyzed reactions for screening purposes. Two examples were investigated: the first one was a lipase catalyzed reaction which produces 2-methoxy-N-[(1R)-1-phenylethyl]acetamide (MET) using rac-alpha-phenylethylamine (PEA) as substrate. The second one was the pyruvate decarboxylase catalyzed formation of (1R)-1-hydroxy-1-phenyl-2-propanone (PAC) with benzaldehyde (BzA) as substrate. Here the corresponding oximes were analyzed after derivatization using hydroxylamine. The standard curves (r2 = 0.985 for MET, r2 = 0.991 for PAC) were linear over two orders of magnitude for MET and PAC concentrations. After optimization of the sample preparation an average relative standard deviation of 12.5% was obtained in both cases.
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PMID:Quantitation of low molecular mass substrates and products of enzyme catalyzed reactions using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. 1108 6

The goal of this study was to determine whether a panel of tumor suppressor gene markers of allelic loss could serve as a representative indicator of gene damage and thereby provide further discriminative power over current staging systems for recurrence-free prognostication in patients undergoing liver transplantation in the presence of hepatocellular carcinoma. The paraffin blocks from 103 cases of hepatocellular carcinoma were obtained, and cellular targets were selected for tissue microdissection genotyping. Tumor suppressor gene loss was based on loss of heterozygosity situated within or adjacent to specific genes of interest (APC, CDKN2A, DCC, MET, MYC1, OGG1, p34, p53, PTEN). Microdissected tissue was amplified using polymerase chain reaction (PCR) with flanking oligonucleotides bearing fluorescent labels designed for GeneScan fragment analysis; PCR products were separated by capillary electrophoresis. Normal microdissected tissue samples for each case were evaluated for informative status with respect to individual alleles for 18 microsatellites at 10 genomic loci-1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, 17q, 18q. The measure of allelic loss of heterozygosity combined with tumor number, tumor size, vascular invasion, lobar distribution, and patient gender provide a highly discriminatory model for predicting cancer recurrence after liver transplantation. Using our previously developed artificial neural network model in combination with the genotyping results, unambiguous predictions were made for 91 of the103 patients (88.3%). Of these, 1 was lost to follow-up, and 9 died recurrence-free less than 3 years posttransplantation. For the remaining 81, the combined models predicted tumor recurrence outcomes with complete accuracy. Microdissection genotyping provides powerful supplementary discriminative information for tumor-free survival.
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PMID:Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. 1282 50

Dysregulated cell growth or differentiation due to misexpression of developmental critical factors seems to be a decisive event in oncogenesis. As osteosarcomas are histologically defined by malignant osteoblasts producing an osteoid component, we prospected in pediatric osteosarcomas treated with OS94 protocol the genomic status of several genes implied in ossification processes. In 91 osteosarcoma cases, we focused on the analysis of the fibroblast growth factor receptors (FGFRs) TWIST, APC, and MET by allelotyping, real-time quantitative polymerase chain reaction, gene sequencing, and protein polymorphism study. Our study supports the frequent role of TWIST, APC, and MET as osteosarcoma markers (50%, 62%, and 50%, respectively). TWIST and MET were mainly found to be deleted, and no additional APC mutation was identified. Surprisingly, FGFRs are abnormal in only < 30%. Most of these factors and their abnormalities seem to be linked more or less to one clinical subgroup, but the most significant correlation is the link of MET, TWIST, and APC abnormalities to a worse outcome and their combination within abnormal tumors. A wider cohort is mandatory to define more robust molecular conclusions, but these results are to be considered as the beginning of a more accurate basis for diagnosis, in search of targeted therapies, and to further characterize prognostic markers.
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PMID:Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis. 1778 87

Altered expression of miRNAs is associated with development and progression of various human cancers by regulating the translation of oncogenes and tumor suppressor genes. In colorectal cancer, these regulators complement the Vogelstein multistep model of pathogenesis and have the potential of becoming a novel class of tumor biomarkers and therapeutic targets. Using quantitative real-time PCR, we measured the expression of 621 mature miRNAs in 40 colorectal cancers and their paired normal tissues and identified 23 significantly deregulated miRNAs. We subsequently evaluated their association with clinical characteristics of the samples and presence of alterations in the molecular markers of colorectal cancer progression. Expression levels of miR-31 were correlated with CA19-9 and miR-18a, miR-21, and miR-31 were associated with mutations in APC gene. To investigate the downstream regulation of the differentially expressed miRNAs identified, we integrated putative mRNA target predictions with the results of a meta-analysis of seven public gene expression datasets of normal and tumor samples of colorectal cancer patients. Many of the colorectal cancer deregulated miRNAs computationally mapped to targets involved in pathways related to progression. Here one promising candidate pair (miR-1 and MET) was studied and functionally validated. We show that miR-1 can have a tumor suppressor function in colorectal cancer by directly downregulating MET oncogene both at RNA and protein level and that reexpression of miR-1 leads to MET-driven reduction of cell proliferation and motility, identifying the miR-1 downmodulation as one of the events that could enhance colorectal cancer progression.
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PMID:miRNA profiling in colorectal cancer highlights miR-1 involvement in MET-dependent proliferation. 2234 15

To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.
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PMID:A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations. 2286 45

Increasing use of fine needle aspiration for oncological diagnosis, while minimally invasive, poses a challenge for molecular testing by traditional sequencing platforms due to high sample requirements. The advent of affordable benchtop next-generation sequencing platforms such as the semiconductor-based Ion Personal Genome Machine (PGM) Sequencer has facilitated multi-gene mutational profiling using only nanograms of DNA. We describe successful next-generation sequencing-based testing of fine needle aspiration cytological specimens in a clinical laboratory setting. We selected 61 tumor specimens, obtained by fine needle aspiration, with known mutational status for clinically relevant genes; of these, 31 specimens yielded sufficient DNA for next-generation sequencing testing. Ten nanograms of DNA from each sample was tested for mutations in the hotspot regions of 46 cancer-related genes using a 318-chip on Ion PGM Sequencer. All tested samples underwent successful targeted sequencing of 46 genes. We showed 100% concordance of results between next-generation sequencing and conventional test platforms for all previously known point mutations that included BRAF, EGFR, KRAS, MET, NRAS, PIK3CA, RET and TP53, deletions of EGFR and wild-type calls. Furthermore, next-generation sequencing detected variants in 19 of the 31 (61%) patient samples that were not detected by traditional platforms, thus increasing the utility of mutation analysis; these variants involved the APC, ATM, CDKN2A, CTNNB1, FGFR2, FLT3, KDR, KIT, KRAS, MLH1, NRAS, PIK3CA, SMAD4, STK11 and TP53 genes. The results of this study show that next-generation sequencing-based mutational profiling can be performed on fine needle aspiration cytological smears and cell blocks. Next-generation sequencing can be performed with only nanograms of DNA and has better sensitivity than traditional sequencing platforms. Use of next-generation sequencing also enhances the power of fine needle aspiration by providing gene mutation results that can direct personalized cancer therapy.
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PMID:Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: promises and challenges for routine clinical diagnostics. 2390 51

Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.
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PMID:Detection of an activated JAK3 variant and a Xq26.3 microdeletion causing loss of PHF6 and miR-424 expression in myelodysplastic syndromes by combined targeted next generation sequencing and SNP array analysis. 2467 52

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1%), as well as in VHL, BRAF, MLH1, TP53 and RET1 (3% each). Moreover, NRAS-, KRAS- and ATM-mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
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PMID:Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm. 2511 87

Identification of multi-gene variations has led to the development of new targeted therapies in lung adenocarcinoma patients, and identification of an appropriate patient population with a reliable screening method is the key to the overall success of tumor targeted therapies. In this study, we used the Ion Torrent next-generation sequencing (NGS) technique to screen for mutations in 89 cases of lung adenocarcinoma metastatic lymph node specimens obtained by fine-needle aspiration cytology (FNAC). Of the 89 specimens, 30 (34%) were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations. Seven (8%) samples harbored KRAS mutations, and three (3%) samples had BRAF mutations involving exon 11 (G469A) and exon 15 (V600E). Eight (9%) samples harbored PIK3CA mutations. One (1%) sample had a HRAS G12C mutation. Thirty-two (36%) samples (36%) harbored TP53 mutations. Other genes including APC, ATM, MET, PTPN11, GNAS, HRAS, RB1, SMAD4 and STK11 were found each in one case. Our study has demonstrated that NGS using the Ion Torrent technology is a useful tool for gene mutation screening in lung adenocarcinoma metastatic lymph node specimens obtained by FNAC, and may promote the development of new targeted therapies in lung adenocarcinoma patients.
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PMID:Next-generation sequencing for molecular diagnosis of lung adenocarcinoma specimens obtained by fine needle aspiration cytology. 2606 7


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