Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinogenesis is the result of a series of genetic mutations resulting in unregulated growth of a clone of cells and the development of malignant lesion that is largely monoclonal though, with the evolution of further genetic changes, there develops a degree of heterogeneity in the tumour. DNA technology, especially allelic imbalance (loss of heterozygosity) studies have identified chromosomal changes in oral carcinoma and head and neck squamous cell carcinoma (SCCHN), suggestive of the involvement of tumour suppressor genes (TSGs), particularly in chromosomes 3, 9, 11 and 17. The regions most commonly identified have included 3p, especially 3p14.2 (FHIT); 3p24, and 3p21.3, where the TSGs involved are as yet unidentified; 9p21 where p16 (INK4A/MTS-1] is the main target TSG; and 17p13 where p53 is the major target TSG. Over-expression of oncogenes, genes mainly involved in cell signalling, especially those on chromosome 11 (PRAD-1 in particular) and 17 (H-ras) and mutations in DNA repair genes, have also been implicated in the carcinogenesis of SCCHN.
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PMID:Genetic aberrations in oral or head and neck squamous cell carcinoma 2: chromosomal aberrations. 1089 69

FHIT (fragile histidine triad), a candidate tumour suppressor gene, has recently been identified at chromosomal region 3p14.2, and deletions of the gene have been reported in many types of human cancer. However, the biological function of the Fhit protein has not been fully characterized yet. Using the yeast two-hybrid screen to search for proteins that interact with Fhit in vivo, we identified a protein that is specifically associated with Fhit. This association was confirmed in both immunoprecipitation and glutathione S-transferase pull-down assays. The sequence of the protein is identical with that of human ubiquitin-conjugating enzyme 9 (hUBC9). The last 21 amino acids at the C-terminus of hUBC9 appear to be unimportant for its biological activity, since an hUBC9 mutant harbouring a deletion of these amino acids could still restore normal growth of yeast containing a temperature-sensitive mutation in the homologue UBC9 gene. Mutational analysis indicated that hUBC9 was associated with the C-terminal portion of Fhit. Neither a single amino acid substitution at codon 96 (His-->Asn) nor triple amino acid substitutions (His-->Asn) at a histidine triad (codons 94, 96 and 98) affected the association, whereas Fhit triphosphate (diadenosine 5',5"'-P(1),P(3)-triphosphate) hydrolase activity has been reported to be eliminated by either type of mutation, suggesting that the interaction between Fhit and hUBC9 is independent of Fhit enzymic activity. Given that yeast UBC9 is involved in the degradation of S- and M-phase cyclins, Fhit may be involved in cell cycle control through its interaction with hUBC9.
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PMID:Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. 1108 38

The FHIT gene, located at the FRA3B fragile site of chromosome 3p14.2, encodes a 16.8 kD homologue of the yeast enzyme diadenosine tetraphosphate (Ap(4)A) hydrolase. Frequent allelic losses at this region in various malignancies, including non-small cell lung carcinomas (NSCLCs), imply that FHIT may represent a tumour suppressor gene (TSG). Increasing evidence suggests that multiple TSG impairment has a synergistic effect on tumour growth. The present study of 67 NSCLCs investigated the allelic imbalance (AIm) within the FHIT locus and its relationship with p53 abnormalities, kinetic parameters [proliferative activity or proliferation index (PI) and apoptotic index (AI)], and ploidy status of the carcinomas. Allelic imbalance at FHIT was observed in 35 out of 55 informative (heterozygous: H) cases (64%). Similar frequencies of loss of heterozygosity (LOH) were noticed among squamous cell lung carcinomas and adenocarcinomas. The high percentage of AIm in stage I tumours (71%) is indicative of its relatively early involvement in NSCL carcinogenesis. No association was found between LOH at FHIT, kinetic parameters, and ploidy status of the tumours. Concurrent loss at FHIT and p53 overexpression [FHIT(LOH)/p53(P)] was the most frequent pattern and was observed in 39% of the informative cases. The latter pattern was not associated with smoking, supporting the hypothesis that in patients with a history of tobacco exposure, FHIT allelic loss may not be a consequence of p53 checkpoint defects, but the outcome of tobacco-induced mutagenesis. Statistically significant differences in the presence of FHIT(LOH)/p53(P) and FHIT(LOH)/p53(N) patterns were noted at the proliferative and apoptotic level, whereas ploidy was similar amongst all groups, implying that wild-type (wt) p53 may play a safeguard role against altered FHIT function. However, the possibility of a masking effect from wt p53 cannot be excluded, since the FHIT(LOH)/p53(P) profile demonstrated a higher growth index (GI=PI/AI mean value ratio) than FHIT(H)/p53(P) (32 vs. 8), although this was not significant. Further studies are needed in order to elucidate the role of FHIT and its relationships with other cell-cycle regulatory molecules involved in NSCL carcinogenesis.
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PMID:Association of allelic loss at the FHIT locus and p53 alterations with tumour kinetics and chromosomal instability in non-small cell lung carcinomas (NSCLCs). 1116 16

Women who develop bilateral breast cancer at an early age are likely to harbour germline mutations in breast cancer susceptibility genes. The aim of this study was to test for concordant genetic changes in left and right breast cancer of young women (age < 50) with bilateral breast cancer that may suggest an inherited breast cancer predisposition. Microsatellite markers were used to test for loss of heterozygosity (LOH) in left and right tumours for 31 women with premenopausal bilateral breast cancer. Markers adjacent to or within candidate genes on 17p (p53), 17q (BRCA1), 13q (BRCA2), 11q (Ataxia Telangiectasia-ATM) and 3p (FHIT) were chosen. Mutational testing for BRCA1 and BRCA2 was performed for cases where blood was available. Concordant LOH in both left and right tumours was demonstrated for at least one of the markers tested in 16/31(54%) cases. Where allelic loss was demonstrated for both left and right breast cancer, the same allele was lost on each occasion. This may suggest a common mutational event. Four cases showed concordant loss of alleles in both left and right breast cancer at D17S791 (BRCA1). BRCA1 mutations were identified in two of these cases where blood was available. Four cases showed concordant LOH at D13S155 (BRCA2). Concordant LOH was further demonstrated in seven cases for D11S1778 (ATM) and four cases for D3S1300 (which maps to the FHIT gene), suggesting a possible role for these tumour suppressor genes in this subgroup of breast cancer patients. No concordant allelic loss was demonstrated for D17S786 suggesting that germline mutations in p53 are unlikely in such cases of bilateral breast cancer.
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PMID:Loss of heterozygosity in bilateral breast cancer. 1120 Jul 74

Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognostic outcome of lung cancer patients has improved only minimally. This is largely due to the inadequacy of the traditional screening approach, which detects only well-established overt cancers and fails to identify precursor lesions in premalignant conditions of the bronchial tree. In recent years this situation has fundamentally changed with the identification of molecular abnormalities characteristic of premalignant changes; these concern tumour suppressor genes, loss of heterozygosity at crucial sites and activation of oncogenes. After considering the morphological modifications that occur in premalignant lesions of the bronchial tree, we analyse the alterations occurring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important sites such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ras, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), and finally the c-myc oncogene. The expression of c-myc is influenced strongly by the presence of growth factors (GFs), among which EGF is of prime importance, as well as its receptor coded for by the c-erbB-2 oncogene. Basic knowledge at the molecular level has extremely important clinical implications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and screening of premalignant lung lesions, such as fluorescence bronchoscopy, endobronchial ultrasound, spiral computed tomography combined with precise spatial localization techniques, should basically change the approach to the problems raised by this disease and allow for an increased discovery rate of incipient lesions. Sequential applications will lead to the identification of individuals/populations at high risk, while the availability of accurate 'intermediate end points' will enable the effects of preventive trials to be monitored. Finally, the same molecular abnormalities may serve as 'starting points' for innovative treatments designed to restore the altered functions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open an era of hope.
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PMID:Molecular genetic abnormalities in premalignant lung lesions: biological and clinical implications. 1143 8

The FHIT (fragile histidine triad) gene on chromosome 3p14.2 is a candidate tumour suppressor gene. To define the role of the FHIT gene in the development of ovarian cancer, we have examined 33 ovarian carcinomas, 2 borderline tumours and 10 benign adenomas for the presence of FHIT gene alterations. FHIT transcripts were analysed by RT-PCR and sequencing. Aberrant FHIT transcripts were observed in 5/33 carcinomas (15%) and in 1 of 2 borderline tumours. Loss of normal FHIT transcript was observed in 5/33 carcinomas (15%) but not in 2 borderline tumours or 10 benign adenomas. Allelic losses at D3S1300 and D3S4103, both located within intron 5 of FHIT, were detected in 5/24 (21%) and 5/25 (20%) informative ovarian carcinomas, respectively. Expression of Fhit protein was analysed by immunohistochemistry in 44 carcinomas, 19 borderline tumours and 16 benign adenomas. Loss or significantly reduced expression of Fhit protein was observed in 6/44 (14%) ovarian carcinomas but not in any of 19 borderline tumours or 16 benign adenomas. The impaired Fhit protein expression was significantly correlated with the loss of normal FHIT transcription. Most notably, loss of normal FHIT transcript and impaired expression of Fhit protein occurred only in serous adenocarcinomas of grade 2 and 3 (5/15; 33% and 6/19; 32%, respectively). The present data suggest that inactivation of the FHIT gene by loss of expression is one of the important molecular events associated with the genesis of ovarian carcinoma, especially of high-grade serous carcinoma.
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PMID:Impaired FHIT expression characterizes serous ovarian carcinoma. 1146 Oct 85

The FHIT gene encodes a diadenosine hydrolase and may be involved in growth control pathways of the cell. Studies on protein-protein interactions, cell lines, including tumourigenicity tests, and knockout mice suggest that the Fhit protein is involved in cell proliferation and apoptosis, and might act as a tumour suppressor. In several different cancers, including breast cancer, alterations in the FHIT gene have been detected in high frequency. The most common alterations are: deletions, DNA hypermethylation, abnormal transcripts and reduced expression at RNA and protein level. The FHIT gene is located at the FRA 3B fragile site at chromosome 3p 14.2, and alterations in the FHIT gene and Fhit protein have been found associated with genome instability, particularly in BRCA 2 mutated breast tumours. This paper will focus on some of the functional aspects of the Fhit protein with respect to tumour pathogenesis and on aberrations detected in breast cancer.
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PMID:FHIT alterations in breast cancer. 1156 78

The majority of hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in DNA mismatch repair genes, especially in MLH1 and MSH2. Tumours in such patients also show microsatellite instability characteristic for DNA repair defects. The FHIT gene, a candidate tumour suppressor gene located at 3p14.2 has been shown to be involved in carcinogenesis of many human tissues, including digestive tract tissues. In our study, we characterized Fhit protein expression in hereditary and sporadic colorectal cancers (CRC). Our intention was to determine if cancers with mutations in the mismatch repair genes, MSH2 and MLH1, would show more frequent inactivation of the FHIT gene. Sixteen HNPCC and 28 sporadic CRC cases were examined by standard immunohistochemical analyses. Both study groups comprised carefully and selectively chosen cases. We have observed higher frequency of loss or reduction of Fhit protein expression in hereditary CRC than in sporadic cases (44% vs. 25%). Although this difference was not statistically significant (p = 0.17), possibly due to the small number of available tumour specimens, the tendency is interesting. More extensive studies on a larger number of cases should be done in the HNPCC group to confirm statistical significance. Our results suggest that the FHIT gene plays an important role in carcinogenesis of at least one fourth of all colorectal cancers.
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PMID:Fhit protein expression in hereditary and sporadic colorectal cancers. 1176 99

The genes specifically involved in endometrial cancers have not yet been discovered. The FHIT gene, a tumour suppressor located at 3p14.2, is altered in many human tumours, including those derived from the female genital tract. We have thus investigated the status of Fhit protein expression in endometrial carcinomas (EC), and its association with histological grade of malignancy in order to determine if Fhit expression is inactivated in EC and if so, whether it is inactivated during initiation or progression. Recent studies have reported that alteration in the FHIT locus detected by DNA and RNA analysis is well correlated with loss of Fhit protein expression in tumours. Thus, we characterised Fhit protein expression as an indication of FHIT gene status in 35 cases of EC of different histological grade (G1: 13 cases; G2: 14 cases; G3: 8 cases). In our group of cancers, Fhit protein expression was absent or reduced in 37% (13/35) of EC. The first 13 cases, judged as G1, showed Fhit deficiency in approximately 38.5% of cases (5/13). For G2 and G3 tumours these numbers were similar and accounted for approximately 35.7% (5/14) and approximately 37.5% (3/8), respectively. No statistical difference was found for Fhit expression among the various groups of tumours, which allowed us to conclude that morphological grade does not seem to be an important factor. Our results suggest that Fhit inactivation is an early event in carcinogenesis of the endometrium. As this observation is contrary to some already published reports, another independent study with larger amounts of material is necessary to determine this issue definitely.
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PMID:Fhit protein expression in endometrial cancers: no correlation with histological grade. 1191 81

The FHIT gene is a putative tumour suppressor gene. In this study, we analysed a set of 50 gastric tumours for alterations of FHIT, and found 38 of 45 tumours (84%) exhibiting loss of heterozygosity (LOH) within the FHIT gene. We used both nested Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and single step RT-PCR to analyse the FHIT transcripts and found 34 of 39 (87%) tumours and seven of the 11 (64%) corresponding non-cancerous tissues showed low or aberrant expression of FHIT mRNA and the appearance of the aberrant FHIT transcripts depended on the conditions of the RT-PCR. In these aberrant transcripts, frequent deletions and/or insertions were detected by direct sequencing. All breakpoints for deletions and insertions were at splicing sites. All insertions came from the adjacent introns, whose appearance was completely in accordance with the 'GU-AG' rule for pre-mRNA splicing. It may be suggested that an alternative splicing mechanism functions in the formation of these aberrant transcripts. The fragile nature of FRA3B within the FHIT gene could be responsible for the formation of the aberrant mRNA. Negative or reduced Fhit expression was detected in 39 of 50 tumours (78%). Moreover, an association was found between abnormal Fhit expression and positive node status (P=0.012). Thirteen of 48 tumours (27%) displayed microsatellite instability (MSI), among which 10 tumours also showed MSI within the FHIT gene. Furthermore, we detected an association between MSI and negative node status (P=0.02). We conclude that the abnormalities of FHIT, presumably associated with the unstable nature of FRA3B within the FHIT gene, are involved in the carcinogenesis of gastric cancer, and lack of mismatch repair (MMR) could possibly promote its alteration in a subset of gastric tumours.
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PMID:High frequency of LOH, MSI and abnormal expression of FHIT in gastric cancer. 1191 57


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