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)

Two genes, namely p27Kip1 and p21WAF/Cip1 that reveal distinct structural homology, have been identified as inductors of cell cycle arrest at the G1-checkpoint to prevent entry of somatic cells into the S phase of the cell cycle when substantial DNA damage has occurred. It was demonstrated that the p21WAF/Cip1 gene is induced by pathways dependent and independent from a functionally intact p53 tumour suppressor protein. It has been suggested that decreased expression both of the p21WAF/Cip1 and p27Kip1 protein may contribute to the development of human malignancies due to loss of critical antiproliferative mechanisms. So far, the role of altered p21WAF/Cip1 and mainly of a decreased p27Kip1 protein expression in patients with muscle invasive bladder cancer has not been investigated. In the present study, 50 tumour specimens from 50 patients undergoing radical cystectomy (T2-T4) were investigated for different biological and clinical characteristics as possible prognostic factors: age, depth of tumour infiltration (T-stage), histological grading (G), lymph node status as well as immunohistochemical staining for the p21WAF/Cip1 and p27Kip1 proteins. The median recurrence-free survival for patients with and without retained p21WAF/Cip1 protein expression was 54 months (3-86 months) and 13 months (1-40 months), respectively (p=0.07). During univariate analysis, loss of p21WAF/Cip1 protein expression (p=0.02), T-stage (p=0.02) and histological grading (p=0.03) were significant prognostic factors for survival, among which a negative reaction for the p21WAF/Cip1 protein (p=0.02) as well as T-stage (p=0.005) remained independent significant predictors during multivariate analysis. Loss of p27Kip1 protein expression was not correlated with the recurrence-free or the overall survival of the patients. Prospective studies are needed to confirm the independent prognostic potential of cell-cycle associated proteins such as p21WAF/Cip1 in patients with muscle invasive bladder cancer. The availability of more refined prognostic factors should assist decision making regarding the value of more aggressive treatment options, such as adjuvant or neoadjuvant chemotherapy, for defined subgroups of patients.
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PMID:Prognostic value of p27Kip1 and p21WAF/Cip protein expression in muscle invasive bladder cancer. 1020 16

Polymorphisms of N-acetyltransferase type 2 (NAT2) conferring the slow acetylator phenotype have been linked to increased susceptibility to arylamine-induced bladder cancer in Caucasians. Genes for NAT2, the other NAT isozyme, NAT1, and a NAT pseudogene (NATP) are found on 8p22, a region displaying loss of heterozygosity, particularly in invasive bladder tumours. A restriction enzyme digestion map has defined the relative positions of the NAT genes to each other and to adjacent CpG islands. NAT2, as a polymorphic gene of known function, is a potentially valuable marker for the detection of loss of heterozygosity in 8p22. Two approaches to investigate loss of heterozygosity at the NAT2 locus in bladder tumours have been used. (1) A cosmid containing NAT2 has been used in fluorescence in-situ hybridization on human exfoliated bladder cells collected from unselected bladder cancer outpatients. Loss of signal from the NAT2 cosmid was found in nine of the 20 patients. (2) A panel of 13 human bladder tumours was investigated for loss of heterozygosity using the polymorphism in the NAT2 gene as a marker. Loss of heterozygosity at the NAT2 locus has been compared with loss of heterozygosity at adjacent microsatellite marker sites known to be located on 8p. There is agreement between loss of heterozygosity at the NAT2 locus and adjacent microsatellite marker loci in 11 of the tumours but two of the tumours appear to show retention at the NAT2 locus. More extensive mapping of the region around the NAT loci, particularly on the centromeric side, is important to pinpoint possible tumour suppressor genes or their modifiers in the region. There are no other expressed sequences known in this region and therefore NAT genes are important genetic landmarks.
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PMID:Genes for human arylamine N-acetyltransferases in relation to loss of the short arm of chromosome 8 in bladder cancer. 1020 36

The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (> or = pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23.
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PMID:Somatic mutation of PTEN in bladder carcinoma. 1036 Jun 73

Small cell carcinomas (SCCs) represent a rare histological subtype of urinary bladder cancer. Little is known abut the genetic alterations in these tumours. To identify chromosomal aberrations that are typically present in SCC of the urinary bladder, ten tumours were analysed by comparative genomic hybridization (CGH). CGH allows screening for all relative DNA copy number gains and losses present in a tumour. SCCs of the bladder were characterized by a high number of genomic alterations (mean: 11.3 per tumour). Deletions were most frequent at 10q (7 of 10 tumours deleted), 4q, 5q (5/10 each), and 13q (4/10). These regions may carry tumour suppressor genes with relevance for this particular tumour type. Gains of DNA sequences were most prevalent at 8q (5/10), 5p, 6p, and 20q (4/10 each). High level amplifications were found at 1p22-32, 3q26.3, 8q24, and 12q14-21. These loci may pinpoint the localization of oncogenes with relevance for small cell bladder cancer. The analysis of one tumour having areas of both SCC and transitional cell carcinoma strongly suggests that SCC can develop from TCC through the acquisition of additional genetic alterations.
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PMID:Chromosomal imbalances in small cell carcinomas of the urinary bladder. 1054 80

A C-->T polymorphism in intron 7 of the human tumour suppressor gene p53 was studied in 159 urinary bladder cancer patients and 171 non-cancer controls. The polymorphism was found in 15% of both patients and controls, suggesting that it has no relevance in urinary bladder cancer pathogenesis or aetiology. A second polymorphism, a T-->G change located 20 bp downstream of the C-->T change, was found in all samples with the C-->T change. Our findings indicate that the C-->T and the T-->G changes occur simultaneously and belong to the same allelotype.
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PMID:p53 intron 7 polymorphisms in urinary bladder cancer patients and controls. Stockholm Bladder Cancer Group. 1064 May 31

Transcriptional silencing by CpG island hypermethylation of gene regulatory regions is one mechanism for inactivation of tumour suppressor genes. Chromosome 9q deletion is frequently found in transitional cell carcinoma (TCC) of the bladder and upper urinary tract and one of the putative tumour suppressor loci has been mapped to 9q32-33. A gene designated as DBCCR1 was identified in the candidate region and its mRNA expression is thought to be suppressed by hypermethylation. To understand the role of hypermethylation in TCC, we evaluated the methylation status of 20 CpG sites of the DBCCR1 5'-CpG island region in a total of 69 tumours from 45 patients, 21 normal urothelial specimens, and six bladder cancer cell lines. Aberrant hypermethylation levels were found in 36 (52%) of 69 tumours without any association with tumour grade or stage. Methylation was weakly detected in the normal urothelium in association with ageing. Although recurrent tumours tended to have higher methylation levels than the initial tumours, the methylation pattern was mostly maintained between multifocal TCCs in individual patients. The results suggest that hypermethylation of the DBCCR1 region is one of the earliest alterations in the development of TCCs and there may be an age-related hypermethylation-based field defect in normal urothelium. Methylator or methylation-resistant phenotype seems to be maintained during multifocal development or recurrence of most TCCs.
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PMID:Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. 1131 84

Bladder cancer is clinically characterized by a high recurrence rate for superficial tumours up to 70% and by the invasiveness of advanced bladder cancer. To learn more about the biological behaviour of an individual bladder cancer different tumour markers have been investigated. The aim of our study was to compare the potential of aggression of both superficial and invasive bladder tumours by means of the proliferation marker Ki67, the tumour suppressor gene p53, the non metastasizing protein nm23 and the evaluation of DNA ploidy. We examined 36 patients, 28 with a bladder tumour (Ta-T4) and 8 without as a control group. For immunohistochemistry (Ki67, p53, nm23) we took paraffin sections and scored semiquantitatively under a microscope. The DNA cytophotometry was done on bladder washings by evaluating the DNA ploidy of single cells. The results showed that benign tissues were negative for Ki67 and p53 but positive for nm23. The DNA diagnosis was diploid for all benign samples. The superficial bladder cancer (Ta, T1) showed, in comparison to the invasive tumours, significantly lower numbers of aneuploid cells and a higher rate of p53 mutations. On the other hand the invasive tumours (T2-4) were correlated to significantly higher proliferation rates and higher potencies for metastasizing. The combination of the investigated tumour markers allowed a graduation of the biological behavior of an individual bladder cancer. Especially a high p53 mutation rate and a non aneuploid DNA diagnosis were indicators for the recurrence of superficial bladder tumours. Invasive growth of bladder cancer was characterized by high Ki67 proliferation and low nm23 protein binding.
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PMID:Immunohistochemical examinations (Ki67, p53, nm23) and DNA cytophotometry in bladder cancer. 1132 61

Deletion of all or part of chromosome 9q is the most common genetic alteration in all stages and grades of bladder cancer. DBCCR1 (deleted in bladder cancer chromosome region candidate 1) maps to the chromosome region 9q32-33, a candidate tumour suppressor locus for bladder cancer. Although no mutations of DBCCR1 have been detected in bladder tumours, expression of DBCCR1 is silenced by promoter hypermethylation in 50% of bladder cancer cell lines analysed. Here we sought to provide functional evidence to authenticate DBCCR1 as a tumour suppressor using gene-transfer methods. Exogenous expression of DBCCR1 protein or an HA epitope-tagged fusion protein, HA-DBCCR1 in NIH3T3 cells and human bladder tumour cell lines resulted in suppression of proliferation. Cell cycle analyses in NIH3T3 cells revealed that DBCCR1-mediated growth inhibition was due to an increase in the number of cells in the G(1) phase of the cell cycle. The levels of apoptosis were not altered. These results demonstrate a role for DBCCR1 in cell cycle control, thereby supporting the hypothesis that this is the tumour suppressor gene targeted by 9q32-33 deletion in bladder cancer.
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PMID:Negative regulation of G(1)/S transition by the candidate bladder tumour suppressor gene DBCCR1. 1142 Jul 8

Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence.
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PMID:Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder. 1192 Jul 32

Allelic loss on chromosome 9q is a very frequent event in bladder carcinogenesis. In recent years, efforts have been directed towards identifying the postulated tumour suppressor genes on this chromosome arm by deletion mapping and mutation analysis. However, no convincing candidate genes have been identified. This paper describes the development of chromosome 9q alterations in multiple recurrent superficial bladder cancers of ten patients and shows that loss of heterozygosity (LOH) on this chromosome is almost never the characteristic first step. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss vary from patient to patient. It is concluded that even if 9q harbours a bladder cancer gatekeeper gene, it is unlikely that the gene will be identified through LOH analysis alone.
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PMID:The random development of LOH on chromosome 9q in superficial bladder cancers. 1237 68


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