Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel gene was identified recently at chromosome 10q23, named PTEN or MMAC1, and based on several criteria it was designated as a potential human tumor suppressor gene. Loss of heterozygosity affecting this region of 10q is observed in several cancer types, especially glioblastoma, and inactivating mutations of the PTEN/MMAC1 gene are found in some of these cancers as well as cell lines and xenografts. Breast cancer is among the tumor types in which mutations are documented, and germline mutations of the gene appear to be responsible for the rare autosomal dominant familial cancer syndrome known as Cowden disease, which includes breast cancer among its clinical features. To further determine the role that PTEN/MMAC1 mutations may play in breast tumorigenesis, the entire coding region was screened for mutations in 54 unselected primary breast cancers. Two mutations were identified, a somatic 2-bp deletion in an apparently sporadic breast cancer, and a germ-line 4-bp deletion in a breast cancer patient with a clinical history consistent with Cowden disease. These data indicate that somatic mutations of PTEN/ MMAC1 occur in only a small fraction of primary breast cancers and confirm the role of this gene in the etiology of Cowden disease. Evidence is also presented suggesting that numerous polymorphisms and missense variants exist in the PTEN/MMAC1 transcript.
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PMID:Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. 928 66

Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma, the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene, PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10 LOH has recently been identified. Here we have investigated 63 glioblastomas for PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA pairs were performed on 14 of these cases and revealed LOH at locations flanking and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the remaining wild-type allele had occurred in the large majority of tumors with PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR amplification was determined to occur at similar frequencies among cases with or without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth-promoting effect resulting from amplification-associated increases in epidermal growth factor receptor signaling is not necessarily dependent on the inactivation of PTEN/MMAC1.
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PMID:PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. 939 44

In the present study, we searched for genetic alterations of the entire coding region of PTEN/MMAC1, a recently isolated candidate tumor suppressor gene, in 178 specimens from Japanese patients with various malignant tumors by the polymerase chain reaction-single strand conformation polymorphism method. The samples consisted of 11 glioblastoma multiformes (GBMs), 14 astrocytomas, 47 breast cancers, 25 non-small cell lung cancers, 9 small cell lung cancers, 8 pancreatic cancers, 24 renal cell carcinomas, 20 ovarian cancers, and 20 metastatic lung tumors from various organs. Only one somatic frameshift mutation at codon 319 was observed in one (9%) of eleven GBMs. Our results suggest that mutation of the PTEN/MMAC1 gene does not play a major role in carcinogenesis, at least in the tumor types from Japanese patients analyzed in this study.
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PMID:Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary. 943 75

Loss of heterozygosity (LOH) observed at polymorphic loci on both arms of chromosome 10 in many human gliomas suggests the presence of multiple tumor suppressor genes on this chromosome. Recently, the PTEN/MMAC1 gene on 10q23 was isolated as one of these putative glioma suppressors. To determine the subchromosomal localization of others, we analysed 79 gliomas for LOH using 30 polymorphic microsatellite markers on the short arm and 10 markers on the long arm of chromosome 10. Twenty tumors showed LOH at all the loci examined, while 17 others showed LOH at loci on a portion of chromosome 10. Deletion mapping of the latters demonstrated that two distinct regions, encompassing genetic distances of 5.6 cM on 10p15 and 5.5 cM on 10p14, were lost frequently. Introduction of chromosomal fragments 10p14-p15, which included the entire region on 10p15 and a portion of that on 10p14 assigned by deletion mapping, into the human glioblastoma cell line T98G through microcell-mediated chromosome transfer markedly suppressed colony forming ability in soft agar compared with parental T98G cells. The combined results of structural and functional analyses strongly suggest that aberrations of the tumor suppressor gene(s) within chromosomal region 10p14-p15 are involved in development of human gliomas.
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PMID:Structural and functional evidence for the presence of tumor suppressor genes on the short arm of chromosome 10 in human gliomas. 946 44

Cowden disease, a dominantly inherited syndrome characterized by a variety of proliferative lesions and predisposition to breast and thyroid cancer, has recently been linked to the polymorphic marker D10S215 on chromosome segment 10q23. Loss of heterozygosity in prostate cancer is linked to the same marker, whereas loss of heterozygosity in glioblastoma, endometrial cancer, and other malignancies also localizes to this region. Most recently, a putative tumor suppressor gene (PTEN/MMAC1) has been identified in the region between D10S215 and an adjacent, more telomeric marker (D10S541) and was found to be altered in breast cancers, prostate cancers, and glioblastomas. We examined 22 invasive breast cancers for loss of heterozygosity in the 10q23 region and found loss in 41% (9/22). There were two distinct regions of loss, including one near the D10S541 marker, with an approximately equal frequency of deletion in each. The observed pattern of deletion is consistent with the presence of a tumor suppressor gene between D10S215 and D10S541. Most of the poorly differentiated carcinomas in the case collection showed loss of heterozygosity in the region near D10S215, suggesting that this loss correlates with a poor prognosis.
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PMID:Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. 949 29

Over the past few years, although much has been learned about the molecular genetics of central nervous system (CNS) tumors, researchers and pathologists are only beginning to understand the scientific basis of the development of these tumors. Data accumulated so far support the division of glioblastoma into two clinical and molecular subsets. Primary or de novo glioblastomas occur in older patients, are clinically aggressive and exhibit epidermal growth factor receptor amplification or overexpression. Secondary glioblastomas develop from pre-existing low-grade astrocytomas, have a more protracted clinical course, and frequently contain p53 mutations. Both types of tumors show deletions of chromosome 10 and possibly mutations of the PTEN/MMAC1 gene as an endstage event. Oligodendrogliomas have been shown to have genetic abnormalities distinct from those of the astrocytic tumors, commonly involving chromosomes 1p and 19q. As regards meningiomas, loss of chromosome 22q and mutations of the neurofibromatosis type 2 gene are frequent events and loss of chromosome 14q and 10q may be seen in atypical or malignant transformation. Such genetic findings, apart from providing a better understanding of neoplastic transformation in brain tumors, are beginning to form the basis of a new approach to neuro-oncology.
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PMID:The molecular genetics of central nervous system tumors. 964 6

The PTEN/MMAC1 gene at 10q23.3, which has dual specific phosphatase activity, is a novel tumor suppressor gene candidate. Various kinds of tumors have mutations in this gene, including glioblastoma, endometrial carcinoma and prostate cancer. We examined 29 cases of primary non-Hodgkin's lymphoma (NHL) for mutations in the PTEN/MMAC1 gene. One case of diffuse large B cell lymphoma had an 11 bp deletion, but the remaining 28 cases showed no mutations in the genome. Two of these 28 cases showed missense mutations in the PTEN/MMAC1 transcripts, but no alterations in the genomic DNA. These mRNA missense variants are similar to PTEN/MMAC1 transcript aberrations which have been reported in patients with breast cancer. These findings suggest that alterations in the PTEN/MMAC1 gene play a role in the pathogenesis of NHL.
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PMID:Mutational analysis of the PTEN/MMAC1 gene in non-Hodgkin's lymphoma. 969 84

Cowden disease, or multiple hamartoma syndrome, is an autosomal dominant inherited cancer syndrome with a high risk of thyroid and breast cancers. Its susceptibility gene has been mapped to chromosome 10q22-23. Because a newly found tumor suppressor gene, PTEN/MMAC1, often mutated in glioblastoma and in prostatic and breast cancers, has been mapped to the same chromosomal locus, it is suspected that it may be the gene responsible for Cowden disease. germline mutations of the gene have been reported in 4 of 5 families with Cowden disease. We performed a genetic analysis of the PTEN/MMAC1 gene in a sporadically found patient with the disease who had no apparent family history of the disease. We found a germline heterozygous mutation of the PTEN/MMAC1 gene in a patient with Cowden disease. The mutation, a C to T substitution of a single base at codon 130, leads to a formation of stop codon, generating a truncated protein lacking both protein phosphatase signature motif and tensin-like domain. Our finding supports the hypothesis of the PTEN/MMAC1 gene as being responsible for Cowden disease even in a sporadic case.
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PMID:A heterozygous germline mutation of the PTEN/MMAC1 gene in a patient with Cowden disease. 985 63

PTEN/MMAC1/TEP1 is a tumor suppressor that possesses intrinsic phosphatase activity. Deletions or mutations of its encoding gene are associated with a variety of human cancers. However, very little is known about the molecular mechanisms by which this important tumor suppressor regulates cell growth. Here, we show that PTEN expression potently suppressed the growth and tumorigenicity of human glioblastoma U87MG cells. The growth suppression activity of PTEN was mediated by its ability to block cell cycle progression in the G1 phase. Such an arrest correlated with a significant increase of the cell cycle kinase inhibitor p27(KIP1) and a concomitant decrease in the activities of the G1 cyclin-dependent kinases. PTEN expression also led to the inhibition of Akt/protein kinase B, a serine-threonine kinase activated by the phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathway. In addition, the effect of PTEN on p27(KIP1) and the cell cycle can be mimicked by treatment of U87MG cells with LY294002, a selective inhibitor of PI 3-kinase. Taken together, our studies suggest that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI 3-kinase/Akt signaling pathway, and one critical target of this signaling process is the cyclin-dependent kinase inhibitor p27(KIP1).
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PMID:PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. 986 Sep 81

PTEN/MMAC1 is a major new tumor suppressor gene that encodes a dual-specificity phosphatase with sequence similarity to the cytoskeletal protein tensin. Recently, we reported that PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits cell migration, spreading, and focal adhesion formation. Here, the effects of PTEN on cell invasion, migration, and growth as well as the involvement of FAK and p130 Crk-associated substrate (p130Cas) were investigated in U87MG glioblastoma cells missing PTEN. Cell invasion, migration, and growth were down-regulated by expression of phosphatase-active forms of PTEN but not by PTEN with an inactive phosphatase domain; these effects were correlated with decreased tyrosine phosphorylation levels of FAK and p130Cas. Overexpression of FAK concomitant with PTEN resulted in increased total tyrosine phosphorylation levels of FAK and p130Cas and effectively antagonized the effects of PTEN on cell invasion and migration and partially on cell growth. Overexpression of p130Cas increased total tyrosine phosphorylation levels of p130Cas without affecting those of FAK; however, although p130Cas could reverse PTEN inhibition of cell invasion and migration, it did not rescue cell growth in U87MG cells. In contrast to FAK, p130Cas could not be shown to interact with PTEN in cells, and it was not dephosphorylated directly by PTEN in vitro. These results suggest important roles of PTEN in the phenotype of tumor progression, and that the effects of PTEN on cell invasion, migration, and growth are mediated by distinct downstream pathways that diverge at the level of FAK.
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PMID:Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. 992 60


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