Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PTEN gene, located on 10q23, has recently been implicated as a candidate tumor suppressor gene in brain, breast and prostate tumors. In the present study, 123 brain tumors, including various grades and histological types of gliomas occurring in children and adults, were analyzed for PTEN mutations by SSCP assay and sequencing. Mutations in the PTEN gene were found in 13 of 42 adult glioblastomas and 3 of 13 adult anaplastic astrocytomas, whereas none of the 21 low-grade adult gliomas or the 22 childhood gliomas of all grades showed mutations. The single medulloblastoma with a mutation was a recurrent tumor that also possessed a p53 mutation. High-grade adult gliomas with PTEN mutations included cases that also contained gene amplification or p53 gene mutations, as well as cases that did not contain either of these abnormalities. There was no obvious relationship between presence of PTEN mutation and survival; however, there was a tendency for PTEN mutations to occur in older age group patients. This analysis suggest that PTEN gene mutations are restricted to high-grade adult gliomas and that this abnormality is independent of the presence or absence of gene amplification or p53 gene mutation in these tumors.
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PMID:PTEN gene mutations are seen in high-grade but not in low-grade gliomas. 933 Oct 72

The second joint conference of the AACR and the EACR held in Oxford from 9-12 September 1997 was successful from many vantage points. While providing an optimal setting in which European and American cancer researchers could meet and exchange information, the conference had an excellent scientific programme which encompassed both methodological updates on important models used in cancer research and presentations of recent key advances in the molecular genetics of cancer. Lower eukaryotes are established model organisms used to elucidate fundamental but complex eukaryotic processes, such as those involved in tumorigenesis and cancer progression, and the progressive availability of their genome sequence makes them even more attractive. Transgenic mouse models are increasingly used not only for the study of one gene of interest but for investigation of the interactions among genes involved in the same pathway. The family of tumour suppressor genes is growing fast and several presentations were devoted to recently identified members such as the Von Hippel-Lindau gene, the FHIT gene and the PTEN gene. The systematic analysis of loss of heterozygosity on multiple loci in tumour specimens can provide the basis for preliminary models of molecular multistep progression in some tumour types, even though this is limited by the high degree of complexity found. Mechanisms of cell cycle regulation and apoptosis continue to be dissected and to constitute a fruitful area of investigation, with important recent insights on the p53-MDM2 autoregulatory loop and on the involvement of E2F-1 in apoptosis.
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PMID:Recent advances in the molecular genetics of cancer. Second joint conference of the American Association of Cancer Research and the European Association of Cancer Research, Oxford, 9-12 September 1997. 954 79

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.
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PMID:A gene for familial juvenile polyposis maps to chromosome 18q21.1. 954 10

Two genes, called BRCA-1 and BRCA-2, have been identified that appear to be responsible for the majority of familial breast cancer syndromes. These genes now play a prominent role in the practice of the surgeon treating breast cancer. Additional genes, PTEN (Cowden disease), MSH1 or MLH2 (HNPCC), and p53 (Li-Fraumeni syndrome) are responsible for other breast cancer syndromes but have not yet entered the clinical arena on a large scale. The risk of breast and ovarian cancer by age 70 in a BRCA-1 mutation carrier is estimated at 55-75% and 16-26 %, respectively, overall, and as high as 87% and 44% in those with a strong family history. The cancer risks associated with BRCA-2 mutations appear to be somewhat lower than those of BRCA-1. BRCA mutations show a strong founder effect. This is best recognized in the Ashkenazi Jewish community, in which the incidence of one of three characteristic mutations is about 2%. In other ethnic groups the pattern of mutations is different, with over 100 distinct mutations throughout the genes having been described. Most mutations so far have been frame-shift or mis-sense mutations, although large deletions have also been described. Thus, in most situations, assessment of the whole coding sequence is required to confirm or exclude a mutation. Guidelines to suggest who is likely to be a mutation carrier are being clarified, but the appropriate management of someone who tests positive remains difficult. Prophylactic mastectomy and oophorectomy are likely to offer substantial gains in life expectancy to mutation carriers, especially for young women with a strong family history. Unfortunately, there are no currently available strategies to eliminate the risk of breast or ovarian cancer. The psychological impact of testing also remains poorly understood, and the danger of various forms of discrimination remain. These factors must be clearly understood by all parties prior to testing. The process of a dynamic, interactive informed consent--much more than a simple printed document--and also counseling are central to the testing process.
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PMID:Breast cancer genes and the surgeon. 957 77

The gemistocytic astrocytoma is a histological variant of diffuse astrocytomas and is characterised by the presence of large, GFAP-expressing neoplastic astrocytes (gemistocytes) and a tendency towards rapid progression to glioblastoma. In this study, we analyzed 28 gemistocytic astrocytomas (mean fraction of gemistocytes, 35.0+/-9.9%) for mutations in the p53 and PTEN (MMAC1) tumour suppressor genes. Single strand conformation polymorphism (SSCP), followed by direct DNA sequencing of p53 exons 5-8, revealed a mutation in 23 of 28 (82%) cases. Regional analysis of four tumours revealed identical p53 mutations in gemistocytic and fibrillary tumour areas. In contrast, none of 15 gemistocytic astrocytomas (WHO Grade II) and only two of 11 (18%) anaplastic gemistocytic astrocytomas (WHO Grade III) contained a PTEN mutation. Of these, one was a 1 bp deletion in codon 345 and the other a 1 bp insertion in intron 4. Differential PCR did not reveal homozygous PTEN deletion in any of the tumours analysed. These results indicate that p53 mutations are a genetic hallmark of gemistocytic astrocytomas, whilst PTEN mutations are absent in low-grade and rare in anaplastic gemistocytic astrocytomas.
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PMID:p53 and PTEN gene mutations in gemistocytic astrocytomas. 965 Jul 46

Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.
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PMID:PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. 969 Jun 72

A tumor cell line, HCC1937, was established from a primary breast carcinoma from a 24-year-old patient with a germ-line BRCA1 mutation. A corresponding B-lymphoblastoid cell line was established from the patient's peripheral blood lymphocytes. BRCA1 analysis revealed that the tumor cell line is homozygous for the BRCA1 5382insC mutation, whereas the patient's lymphocyte DNA is heterozygous for the same mutation, as are at least two other family members' lymphocyte DNA. The tumor cell line is marked by multiple additional genetic changes including a high degree of aneuploidy, an acquired mutation of TP53 with wild-type allele loss, an acquired homozygous deletion of the PTEN gene, and loss of heterozygosity at multiple loci known to be involved in the pathogenesis of breast cancer. Comparison of the primary tumor with the cell line revealed the same BRCA1 mutation and an identical pattern of allele loss at multiple loci, indicating that the cell line had maintained many of the properties of the original tumor. This breast tumor-derived cell line may provide a useful model system for the study of familial breast cancer pathogenesis and for elucidating BRCA1 function and localization.
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PMID:Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. 969 48

We investigated the dynamics of the genetic changes that are associated with two types of glioma recurrence, that is, progression from a lower-grade to a high-grade tumor (7 cases) and development of a same high-grade recurrence (15 cases). Each pair of tumors was analyzed for TP53 mutation, EGFR amplification, and loss of heterozygosity for tumor suppressor genes (TP53, RB1, CDKN2A, PTEN, DMBT1) and tumor suppressor gene regions (1p36, 19q13, 11p15, 10p15) known to be frequently implicated in glioma tumorigenesis. By comparing the genetic changes in the primary and corresponding secondary tumors, we found that additional loss of CDKN2A and/or RB1, encoding important components of the cell cycle regulatory pathway, was the most frequent genetic change in both types of recurrence development (10 of 22 cases, 45%). Additional loss of heterozygosity for the 10p15 region, for PTEN, and/or for DMBT1 in the recurrent tumor was noted in 7 of 22 cases (32%), suggesting that additional inactivation of tumor suppressor genes on chromosome 10 is another important feature of glioma relapse. Less frequent additional losses were detected for chromosome regions 11p15 and 19q13 (3 of 22 cases, 14%, each). We conclude that glioma recurrences are characterized by an increased involvement of tumor suppressor genes, even in those cases in which the primary and secondary tumor are of the same high malignancy grade.
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PMID:Dynamics of genetic alterations associated with glioma recurrence. 973 18

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.
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PMID:Germline PTEN mutations in Cowden syndrome-like families. 983 31

Mutation of the PTEN tumor suppressor gene is a frequent event in endometrial cancers. In other types of cancers, PTEN mutation has been associated with metastatic behavior and advanced stage. To examine the relationship between PTEN mutation and clinical features of endometrial cancers, we screened 136 cases for mutations in the nine exons and intronic splice sites of the PTEN gene, using single-strand conformation analysis, and aberrant bands were sequenced. Mutations were noted in 44 of 136 (32%) endometrial cancers, and two mutations were present in 8 cases. There were 36 cases with mutations resulting in truncated protein products, 6 cases with missense mutations in the phosphatase domain, 1 case with an in-frame deletion, and 1 case with a large insertion. Mutation of the PTEN gene correlated most closely with endometrioid histology; mutations were seen in only 5% (1 of 21) of serous/clear cell cancers compared with 37% (43 of 115) of endometrioid cancers (P = 0.004). PTEN mutation was associated with early stage, nonmetastatic disease and more favorable survival in both the entire group of 136 cases and in the 115 endometrioid cases. In addition, PTEN mutation correlated with other molecular features associated with favorable clinical behavior, including microsatellite instability and absence of p53 overexpression. Microsatellite instability was found in 60% of cases with PTEN mutations compared with only 25% of cases without mutations (P = 0.004). Overexpression of p53 was seen in only 14% of cases with PTEN mutations compared to 39% of cases without mutations (P = 0.006). In conclusion, PTEN mutation is associated with endometrioid histology and other favorable pathological, clinical, and molecular features rather than with increased metastatic potential as has been noted in some other types of cancers.
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PMID:PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. 986 13


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