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: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clear cell renal cell carcinomas (RCCs) are characterized by a deletion of chromosome 3p, which might result in the inactivation of the FHIT (fragile histidine triad) gene, a putative tumour suppressor gene. To explore the relevance of FHIT aberrations for tumour progression and prognosis in clear cell RCCs, FHIT protein expression was analysed in formalin-fixed tissue from 149 clear cell RCCs by immunohistochemistry. FHIT protein expression was found to be markedly reduced in all RCCs, when compared with adjacent non-neoplastic tubule epithelia. Although remaining below the FHIT levels of normal tubule epithelia, a significant increase of FHIT expression became evident from well (G1) to poorly (G3) differentiated clear cell RCCs (p=0.0001) and from low (pT1) to advanced (pT3) tumour stages (p=0.001). The log-rank test demonstrated a significant inverse correlation (p=0.0074) between FHIT expression and tumour aggressiveness as indicated by patient survival. Cox regression analysis revealed that FHIT expression is an independent prognostic parameter (p=0.0139) in clear cell RCCs. In conclusion, clear cell RCCs show a marked reduction of FHIT protein expression when compared with their putative cells of origin. In contrast to other tumour types, however, loss of FHIT protein expression is significantly less pronounced in poorly differentiated RCCs or advanced tumour stages. This versatility of FHIT expression during tumour progression suggests a role for reversible mechanisms of FHIT inactivation during the initiation and progression of clear cell RCCs.
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PMID:FHIT expression in clear cell renal carcinomas: versatility of protein levels and correlation with survival. 1192 Jul 39

Human malignant mesothelioma (MM) is a highly aggressive neoplasm related to occupational asbestos exposure and characterised by a long latency period between the exposure and onset of disease. Previous studies indicate that losses at different genomic regions are present in MM. We examined allele loss at three known tumour suppressor gene regions (22q/NF2 gene, 9p/p16 gene, and 3p/FHIT gene) and at two other frequently deleted areas (14q and 6q) in MM. Loss of heterozygosity (LOH) was investigated in cell cultures and primary tumours with several highly polymorphic markers for each site. To study if LOH of the NF2 gene is a consistent feature in MM, we performed a more detailed analysis of chromosome 22q that included a NF2 marker (NF2CA3). We observed a high frequency of LOH occurring simultaneously at multiple loci. In particular, 100% of the cultured MM cells exhibited LOH at the NF2 gene region. From the other chromosomal sites analysed, recurrent allele loss was detected at 9p (5/7; 71%), 3p (4/7; 57%), 14q (3/7; 43%), and 6q (3/7; 43%). Of the 32 tumours, even those trimmed to exclude normal tissue, few showed LOH, suggesting consielment by normal cells within MM tumours, whereas tumour cells in primary cultures showed LOH already in passages 1-2. In conclusion, our present LOH data indicate that MM cells exhibit allele losses at multiple tumour suppressor gene sites concurrently, involving NF2 gene preferentially. This supports the view that the accumulation of multiple genetic hits is characteristic to malignant transformation of MM cells.
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PMID:Concurrent LOH at multiple loci in human malignant mesothelioma with preferential loss of NF2 gene region. 1216 54

Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.
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PMID:Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. 1254 68

The loss of tumour suppressor genes (TSGs) is a key event in many human cancers, including gastric carcinoma. Many TSG candidates have been studied, but their roles in gastric carcinogenesis remain unclear. To clarify the clinical significance of TSG expression in gastric carcinoma, the expression of various TSG candidates (p53, E-cadherin, FHIT, smad4, rb, VHL, PTEN, MGMT, p16, and KAI1), as well as other proteins (bcl-2, MUC1, MUC2, MUC5AC, MUC6, CEA, CD44, beta-catenin, C-erbB2, and cyclin B2), was evaluated immunohistochemically in 329 consecutive gastric carcinomas using the tissue array method. The overexpression of p53 and MUC1 (p < 0.01) and the loss of expression of smad4 (p = 0.04), FHIT (p = 0.03), MGMT (p = 0.01), E-cadherin, KAI1, and PTEN (p < 0.01) were found to be significantly associated with poor gastric carcinoma prognosis. Seven out of eight survival-associated proteins were found to be protein products of TSGs. The gastric carcinomas were divided into five groups according to the grade of alteration in TSG expression. No TSG expression loss was found in 32 cases (TSG1). One TSG loss was found in 47 cases (TSG2), two in 67 cases (TSG3), three or four in 64 cases (TSG4), and five, six, or seven in 38 cases (TSG5). The grade of TSG expression was confirmed to be significantly associated with WHO classification (p = 0.04), pTNM stage, lymphatic invasion, and patient survival (p < 0.01 for the latter three). By multivariate analysis, the grade of TSG expression was found to be significantly and independently associated with patient survival (p < 0.01). In conclusion, the findings of this study suggest that the cumulative loss of TSG expression in gastric carcinoma is important in determining patient survival.
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PMID:Tumour suppressor gene expression correlates with gastric cancer prognosis. 1269 39

The FHIT gene encompassing the most active common human chromosomal fragile region, FRA3B, was discovered in 1996 and proposed as a tumour suppressor gene for important human cancers. Seven years and more than 350 reports later, early questions concerning its tumour suppressor role have been answered. Recent studies on the role of Fhit loss in major types of human cancers report association with high proliferative and low apoptotic indices, node positivity, loss of mismatch repair protein, likelihood of progression and reduced survival.
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PMID:Cancer and the FRA3B/FHIT fragile locus: it's a HIT. 1277 12

Chromosome arm 8p is one of the most frequently altered regions in human cancers. Several potential oncogenes and tumour suppressor genes have been identified but further investigations are needed to confirm which are bona fide oncogenic targets. In cancer cells, chromosome breaks may occur at fragile sites throughout the genome. Some fragile sites lie within genes that may have a role in cancer; the best example is FHIT at 3p14, which contains the fragile site FRA3B. We have found that chromosome breaks disrupt the NRG1 gene at 8p12 in breast and pancreatic cancers. We hypothesise that alteration of the NRG1 gene could occur through breakage at a non-common fragile site.
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PMID:Chromosome arm 8p and cancer: a fragile hypothesis. 1476 8

Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM.
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PMID:Reduced Fhit protein expression in human malignant mesothelioma. 1456 98

Array-based comparative genomic hybridization (aCGH) allows the identification of DNA sequence copy number changes at high resolution by co-hybridizing differentially labelled test and control DNAs to a micro-array of genomic clones. The present study has analysed a series of 23 formalin-fixed, paraffin wax-embedded tissue samples of Barrett's adenocarcinoma (BCA, n = 18) and non-neoplastic squamous oesophageal (n = 2) and gastric cardia mucosa (n = 3) by aCGH. The micro-arrays used contained 287 genomic targets covering oncogenes, tumour suppressor genes, and DNA sequences localized within chromosomal regions previously reported to be altered in BCA. DNA sequence copy number changes for a panel of approximately 50 genes were identified, most of which have not been previously described in BCA. DNA sequence copy number gains (mean 41 +/- 25/BCA) were more frequent than DNA sequence copy number losses (mean 20 +/- 15/BCA). The highest frequencies for DNA sequence copy number gains were detected for SNRPN (61%); GNLY (44%); NME1 (44%); DDX15, ABCB1 (MDR), ATM, LAMA3, MYBL2, ZNF217, and TNFRSF6B (39% each); and MSH2, TERC, SERPINE1, AFM137XA11, IGF1R, and PTPN1 (33% each). DNA sequence copy number losses were identified for PDGFB (44%); D17S125 (39%); AKT3 (28%); and RASSFI, FHIT, CDKN2A (p16), and SAS (CDK4) (28% each). In all non-neoplastic tissue samples of squamous oesophageal and gastric cardia mucosa, the measured mean ratios were 1.00 (squamous oesophageal mucosa) or 1.01 (gastric mucosa), indicating that no DNA sequence copy number chances were present. For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH). These data show the sensitivity of aCGH for the identification of DNA sequence copy number changes at high resolution in BCA. The newly identified genes may include so far unknown biomarkers in BCA and are therefore a starting point for further studies elucidating their possible role in Barrett's carcinogenesis.
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PMID:Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. 1522 37

To identify functions of the fragile tumour suppressor gene, FHIT, matched pairs of Fhit-negative and -positive human cancer cell clones, and normal cell lines established from Fhit -/- and +/+ mice, were stressed and examined for differences in cell cycle kinetics and survival. A larger fraction of Fhit-negative human cancer cells and murine kidney cells survived treatment with mitomycin C or UVC light compared to matched Fhit-positive cells; approximately 10-fold more colonies of Fhit-deficient cells survived high UVC doses in clonigenic assays. The human cancer cells were synchronised in G1, released into S and treated with UVC or mitomycin C. At 18 h post mitomycin C treatment approximately 6-fold more Fhit-positive than -negative cells had died, and 18 h post UVC treatment 3.5-fold more Fhit-positive cells were dead. Similar results were obtained for the murine -/- cells. After low UVC doses, the rate of DNA synthesis in -/- cells decreased more rapidly and steeply than in +/+ cells, although the Atr-Chk1 pathway appeared intact in both cell types. UVC surviving Fhit -/- cells appear transformed and exhibit >5-fold increased mutation frequency. This increased mutation burden could explain the susceptibility of Fhit-deficient cells in vivo to malignant transformation.
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PMID:Fhit-deficient normal and cancer cells are mitomycin C and UVC resistant. 1549 23

Squamous cell carcinoma of the head and neck (HNSCC) is a heterogeneous but largely preventable disease with complex molecular abnormalities. It arises from a premalignant progenitor followed by outgrowth of clonal populations associated with cumulative genetic alterations and phenotypic progression to invasive malignancy. These genetic alterations result in inactivation of multiple tumour suppressor genes and activation of proto-oncogenes, including p16(ink4A), p53, cyclin D1, p14(ARF), FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb. Intramucosal migration and clonal expansion of transformed cells with formation of abnormal genetic fields appear to be responsible for local recurrences and development of second primary tumours.
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PMID:Molecular biology of squamous cell carcinoma of the head and neck. 1664 82


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