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)

Hereditary multiple exostoses (HME) is traditionally described as a skeletal dysplasia. However, the discovery that the EXT family of tumour suppressor genes are responsible for HME suggests that it is more appropriate to classify HME as a familial neoplastic trait. In a clinical and radiographic analysis of paired bone length and exostoses number and dimensions in a HME cohort, the local presence of osteochondromas was consistently associated with growth disturbance. In particular, an inverse correlation between osteochondroma size and relative bone length (p<0.01) was found. These data suggest that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect. This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance.
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PMID:Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses. 1073 91

Seventy malignant, premalignant and histologically normal biopsies from 7 oesophagogastrectomy specimens of adenocarcinomas of the lower oesophagus and gastroesophageal junction were analysed for loss of heterozygosity (LOH) at 9 known or putative gene loci. LOH was detected in 20 of 27 (74%) malignant biopsies, 4 of 7 (57%) biopsies of dysplasia, 2 of 12 (25%) biopsies of histologically normal oesophagus adjacent to adenocarcinoma, and in 2 of 14 (14%) biopsies of histologically normal stomach adjacent to adenocarcinoma. LOH at the VHL, APC, CDKN2 and DCC tumour suppressor and MSH3 mismatch repair gene loci can be detected in histologically normal tissue and in adjacent adenocarcinoma, and are potential markers of early neoplastic progression.
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PMID:Histological and molecular mapping of adenocarcinoma of the oesophagus and gastroesophageal junction: loss of heterozygosity occurs in histologically normal epithelium in the oesophagus and stomach. 1076 62

p53 is a tumour suppressor gene encoding a protein whose function is impaired in a very large proportion of human cancers. The objectives of this study were to determine the natural history of p53 alterations during stages of oral carcinogenesis, by comparing p53 immunoexpression in oral squamous cell carcinomas (OSCCs), their non-malignant adjacent mucosa, and respective metastases; and to define the potential practical consequences for clinical management of p53 staining in the non-malignant adjacent mucosa. Forty-two samples of non-malignant mucosa adjacent to OSCCs, the respective carcinomas, and six lymph node metastases derived from six of the OSCCs were investigated for p53 protein expression by immunohistochemistry. Seven out of 42 (17%) non-malignant mucosal samples immediately adjacent to OSCC showed suprabasal p53 staining and this was significantly associated with moderate/severe dysplasia (p=0.02). In six of these cases (86%), the respective carcinoma showed p53 immunoexpression in more than 50% of the neoplastic cells and in the remaining case, p53 immunoexpression was found in more than 25% of the neoplastic cells. In all p53-negative carcinomas that showed p53 immunoexpression in the non-malignant adjacent mucosa, p53 staining was never detected above the basal cell layer. Lymph node metastases showed the same patterns of p53 immunoexpression as the carcinomas from which they were derived. When suprabasal p53 staining is present in non-malignant mucosa immediately adjacent to OSCCs, this suggests stable p53 alterations which are maintained upon progression to overt malignancy. The immunostaining in non-malignant mucosa of the resection margins of OSCCs might be a valuable predictor for local recurrences and may therefore have implications for the management of patients who have received surgical treatment for OSCC.
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PMID:p53 immunoexpression in non-malignant oral mucosa adjacent to oral squamous cell carcinoma: potential consequences for clinical management. 1086 71

The prevalence of Barrett's oesophagus has risen over a short time interval implying environmental in addition to genetic aetiological factors. Bile salt effects from duodenogastro-reflux are assuming increasing importance with deoxycholic and taurodeoxycholic acid being particularly associated with Barrett's oesophagus. The cellular biology changes appear to follow a progression from initial inflammation and oesophagitis to metaplasia and dysplasia through to adenocarcinoma. Mechanisms of restitution include epidermal growth factor mediated increases in epithelial thickness. This results in basal stem cells becoming superficially placed and exposed further to luminal refluxed bile salts. Immature stem cells result which undergo mutation to a metaplastic glandular phenotype with intestinal metaplasia. P53 mutation increasingly occurs in progression to dysplasia and carcinoma and may confer a survival advantage of these cell clones by delaying apoptosis. Cell cycling gene mutations occur with accumulation of cells in G2 phase. Disruption of cellular checkpoint mechanisms in the mitotic process result in loss of heterozygosity and aneuploidy including loss of the Y chromosome. Identical mutations between adjacent areas of dysplasia and adenocarcinoma supports clonal expansion as the mechanism of carcinogenesis. APC tumour suppressor gene mutations are conserved in synchronous carcinomas in Barrett's dysplasia and are associated with beta-catenin accumulation in the nucleus and cellular migration with invasion. Cumulative genetic errors result in abnormal clones with metastatic or angiogenic potential. When a clone with malignant potential occurs adenocarcinoma can result completing the progression from inflammation to metaplasia and dysplasia through to adenocarcinoma.
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PMID:Genetic versus environmental interactions in the oesophagitis-metaplasia-dysplasia-adenocarcinoma sequence (MCS) of Barrett's oesophagus. 1090 14

The degree of DNA-instability as revealed by the immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (DNA-instability test) was used as a marker of malignancy. This was applied to mild dysplasia (42 cases), moderate dysplasia (43 cases), severe dysplasia (27 cases), squamous cell carcinoma in situ (CIS) (21 cases), invasive squamous cell carcinoma (SCC) (31 cases) and normal (7 cases) human uterine cervix. The expression of tumour suppressor gene p53 and oncogene bcl-2 was detected immunohistochemically. Proliferative activity was evaluated by PCNA immumohistochemistry and the quantitative analysis of the number, mean area, the largest area and maximum shape irregularities of AgNOR in a nucleus were performed for all these cases. The distribution of numeric chromosomal aberrations of chromosome 17 was also investigated in some of these cases. The results showed that 31 SCC (100%), 21 CIS (100%), 21 severe dysplasia (77.77%), 28 moderate dysplasia (65.11%), and 14 mild dysplasia (33.33%) were positively stained by the DNA-instability test diffusely or sporadically, indicating their malignancy. Reflecting the malignant character, these cases showed a remarkable increase in the PCNA-index with the loss of polarity of PCNA positive cell distribution and also an increase in number, mean and largest sizes and maximum shape irregularity of AgNOR dots. The mean chromosome index for chromosome 17, p53 and bcl-2 immunostaining positivity were also found to be significantly increased in moderate and severe dysplasia and in cancerous cases in comparison to normal and mild dysplasia cases. Moreover, the DNA-instability-test positive dysplasia cases showed statistically significant increased values of PCNA-index, AgNOR parameters, mean chromosome index, p53 and bcl-2 expression in comparison to those of DNA-instability-test negative dysplasia cases. In conclusion, some mild dysplasia (33.33%) and most of the moderate (65.11%) and severe dysplasia (77.77%) were regarded as malignant in nature, existing at an early stage of progression of malignancy.
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PMID:Early progression stage of malignancy of uterine cervical dysplasia as revealed by immunohistochemical demonstration of increased DNA-instability. 1096 62

Squamous epithelial dysplasia is often observed multifocally in the cancerous oesophagus and is presumably considered to be a pre-cancerous lesion. A mutation of the p53 tumour suppressor gene is commonly identified in oesophageal cancer and dysplasia. p53 mutations can be anticipated immunohistochemically. In order to confirm the biological and clinical significance of p53 expressions in oesophageal field carcinogenesis, immunostaining for p53 in cancerous and multifocal precancerous lesions from resected human oesophagus was systematically investigated, while paying special attention to the contiguity of these lesions. Lesions expressing p53 were detected in 46.5% (20 of 43 lesions) of the invasive carcinoma, and in 51.0% (46 of 90 lesions) of the carcinoma in situ, and in 51.4% (92 of 179 lesions) of the dysplasia. Next, the p53 expression in dysplasia was compared with that in carcinoma for the same case. 37 of 39 (94.8%) dysplasias contiguous to p53-positive carcinomas also expressed p53 (P<0.0001). On the other hand, the isolated dysplasias without contiguity to p53-positive carcinomas, only expressed p53 protein in 44.0% (11 of 25 lesions). No significant correlations were found between the p53 staining and either the clinicopathological features or prognosis. Discordant p53 alterations, such as those seen in cancerous and isolated precancerous lesions, may thus demonstrate further evidence for a multicentric or field carcinogenesis of the human oesophagus.
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PMID:p53 expression in squamous dysplasia associated with carcinoma of the oesophagus: evidence for field carcinogenesis. 1099 51

The cyclin-dependent kinase (cdk) inhibitor, p57 (Kip2) is a tumour suppressor candidate and a paternally-imprinted gene. In humans, the p57(Kip2) gene is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome. From analysis of p57(Kip2)-deficient mice, we demonstrate the relationship between trophoblastic abnormalities and p57(Kip2). Both p57(Kip2) null ((-/-)) embryos and heterozygous embryos with a maternally-derived mutated allele ((+*/-)) displayed placentomegaly, as well as dysplasia of labyrinthine and spongiotrophoblasts. The number of labyrinthine trophoblasts of homozygous embryos was twice that in wild-type embryos. When we measured kinase activities of cdk in total placenta lysates by the immuno complex kinase assay, there were no differences among the genotypes. These results show that p57(Kip2) may function in the proper development of labyrinthine and spongiotrophoblasts by pathways that are not involved with regulation of cdk activities. It is, therefore, suggested that p57(Kip2) protein might have an unknown role.
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PMID:p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. 1104 65

Interleukin-10-deficient mice develop colitis and colorectal cancer similar to the inflammatory bowel disease associated cancer in humans. The aim of this study was to identify possible mutations of oncogenes and tumour suppressor genes involved in tumorigenesis in Interleukin-10 (IL-10)-deficient mice. Twenty colon carcinomas from IL-10-deficient mice were screened for mutations in the K-ras and p53 genes by 'cold' single-strand-conformation polymorphism. Immunohistochemical staining was performed to detect mutations in the proteins P53, APC and MSH2, and the transforming growth factor beta type II receptor. Microsatellite instability was analysed at eight chromosomal loci and plasma levels of transforming growth factor beta1 (TGF-beta1) were also measured. At 9 weeks, 14% of the animals developed colorectal cancer, and at 10-31 weeks the incidence of carcinoma was 65%. No mutations were detected in the analysed oncogene and tumour suppressor genes. Plasma TGF-beta1 levels in IL-10-deficient mice 10-31 weeks old were higher than in wild-type littermates e.g. 45.7 +/- 4.6 ng/ml versus 19.8 +/- 4.5 ng/ml (P<0.01). No alterations in K-ras, p53, APC: and Msh2 genes suggests that other genes are involved in the development of these tumours. Elevated TGF-beta1 plasma levels correspond to the high incidence of dysplasia and cancer. Normal expression of the TGF-beta II receptors hints at genetic alterations in other members of the TGF-beta receptor signal transduction pathway.
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PMID:Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. 1128 4

4p16.3 has previously been identified as a region of non-random LOH in transitional cell carcinoma, suggesting the presence of a tumour suppressor gene. One candidate within this region is fibroblast growth factor receptor 3 (FGFR3). Germline mutations in FGFR3 are known to cause several autosomal dominant skeletal dysplasias, the severity of which depends on the position and nature of the mutation in the protein. We investigated the frequency and nature of FGFR3 mutations in a panel of transitional cell carcinomas and cell lines and studied the possible link between mutation and loss of heterozygosity (LOH) on 4p16.3. FGFR3 coding sequence from 63 transitional cell carcinomas (TCC) of various stages and grades, and 18 cell lines was analysed by fluorescent SSCP. Samples with abnormal migration patterns were sequenced to identify the mutation or polymorphism. Thirty-one of the 63 tumours had previously been assessed to have LOH at 4p16.3. Twenty-six of the 63 tumours (41%) and 4/18 (22%) of the cell lines had missense mutations in FGFR3. All mutations detected in our panel have been reported in the germline where all apart from one cause lethal conditions. One tumour contained K652Q which has recently been identified in less severe cases of skeletal dysplasia. Tumours with and without LOH at 4p16.3 had mutations in FGFR3 suggesting that these two events are not causally linked. The frequency of FGFR3 mutation indicates that this protein plays an important role in TCC.
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PMID:Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. 1131 2

Barrett's oesophagus is a premalignant condition whose incidence is rising dramatically. Molecular markers are urgently needed to identify Barrett's patients at the highest risk of cancer progression. To this end, we have used a rapid molecular technique, restriction site mutation (RSM), to detect low-frequency mutations in the p53 tumour suppressor gene in premalignant Barrett's tissues of cancer-free patients. In total, 38 endoscopically diagnosed Barrett's patients with a range of histological stages of Barrett's progression, plus four control patients without Barrett's oesophagus, were analysed for early p53 mutations. Tissue samples taken from these patients (93 samples in total) were analysed for the presence of low-frequency p53 mutations at hotspot codons: 175, 213, 248, 249, 282. In total, 13 of the 38 Barrett's patients were shown to possess a p53 mutation in at least one sample (no mutations in the four control patients). Although no statistically significant associations were found, p53 mutations reflected histological progression in Barrett's patients with p53 mutations found in 30% of metaplasia patients (P=0.4) and low-grade dysplasia patients (P=0.33) and 45% of high-grade dysplasia patients (P=0.15). Detected p53 mutations were mainly GC to AT transitions at CpG sites.
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PMID:Early p53 mutations in nondysplastic Barrett's tissue detected by the restriction site mutation (RSM) methodology. 1269 95


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