Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MMAC1/PTEN gene, located at 10q23.3, is a candidate tumor suppressor commonly mutated in glioma. We have studied the pattern of deletion, mutation, and expression of MMAC1/PTEN in 35 unrelated melanoma cell lines. Nine (26%) of the cell lines showed partial or complete homozygous deletion of the MMAC1/PTEN gene, and another six (17%) harbored a mutation in combination with loss of the second allele. Mutations could also be demonstrated in uncultured tumor specimens from which the cell lines had been established, and cell lines derived from two different metastases from one individual carried the same missense mutation. Collectively, these findings suggest that disruption of MMAC1/PTEN by allelic loss or mutation may contribute to the pathogenesis or neoplastic evolution in a large proportion of malignant melanomas.
 ...
PMID:Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. 928 67

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.
 ...
PMID:Dynamics of genetic alterations associated with glioma recurrence. 973 18

A candidate tumour suppressor gene, PTEN, has recently been identified within chromosome 10q23, the locus of the Cowden syndrome/Lhermitte Duclos disease susceptibility gene. Cowden disease is an autosomal dominant cancer predisposition syndrome associated with tumours of the breast, thyroid and, less frequently, malignant melanoma. Based on the identification of mutations in sporadic breast, brain and prostate tumours, we decided to examine the potential role of PTEN in sporadic malignant melanoma. Frozen tissue from primary cutaneous melanomas (n = 23) and metastases (n = 17) were microdissected, and microsatellite markers D10S541 and D10S547, flanking the gene on both sides, were used to search for loss of heterozygosity (LOH) in the PTEN gene locus. To identify mutations within the putative tumour suppressor gene, we performed single strand conformation polymorphism (SSCP) analysis using intronic primers to amplify exons 5, 6, 7 and 8 of the PTEN gene. No LOH was detected using the polymorphic markers D10S541 and D10S547. SSCP analysis revealed no aberrant bands in the tumour specimen. Our results suggest that the PTEN gene does not play a major role in the initiation and progression of melanoma.
 ...
PMID:The PTEN tumour suppressor gene and malignant melanoma. 976 4

Mutations of the human putative protein tyrosine phosphatase (PTEN/MMAC1) gene at chromosome 10q23 have been found frequently in type I endometrial carcinomas. Endometrioid adenocarcinoma is the most frequent histology seen in patients with clinically determined synchronous endometrial and ovarian carcinomas. We report a high incidence of PTEN/MMAC1 mutations and 10q23 loss of heterozygosity (LOH) in patients with synchronous endometrial and ovarian carcinomas. Paraffin-embedded precision microdissected tumors were analyzed for 10 matched synchronous endometrial and ovarian cancers and 11 matched control metastatic endometrial cancers. Single-stranded conformation polymorphism analysis was used to screen for mutations in all tumors and corresponding normal lymphocyte DNA. LOH was determined using a panel of four microsatellite markers within the PTEN/MMAC1 locus. PTEN/MMAC1 mutations were found in 43% (9 of 21) of the endometrial cancers studied, similarly represented in the clinically synchronous group (5 of 10 or 50%) and the advanced metastatic group (4 of 11; 36%; P = 0.53). In two of the five cases of clinically synchronous cancers, identical or progressive PTEN mutations were found in both the endometrial and ovarian cancers, suggesting that the ovarian tumor is a metastasis from the endometrial primary. PTEN/MMAC1 mutations in the advanced endometrial cancers were similar in the corresponding metastases. In one case, the mutation was seen in only one of two metastatic lymph nodes. The LOH analysis demonstrated 55% LOH in at least one PTEN/MMAC1 marker. These findings suggest that the putative tumor suppressor gene PTEN/MMAC1 may be a viable molecular marker to differentiate synchronous versus metastatic disease in a subset of clinically synchronous endometrial and ovarian carcinomas.
 ...
PMID:Loss of heterozygosity and mutational analysis of the PTEN/MMAC1 gene in synchronous endometrial and ovarian carcinomas. 1077 94

The PTEN tumor suppressor gene encodes a dual-specificity protein phosphatase that may play a key role in modulating integrin-mediated signals. Inactivation of the PTEN gene has been detected in a small percentage of clinically localized prostate cancers but is common in metastatic disease. It has been shown in glioblastoma cell lines that loss of chromosome 10q, where the PTEN gene is located, is associated with increased angiogenic activity in the conditioned medium attributable to downregulation of thrombospondin-1, a negative regulator of angiogenesis. Therefore, we wished to determine whether inactivation of PTEN might be associated with increased angiogenesis in prostate cancers, because increased angiogenesis in localized cancers is associated with development of metastatic disease. Angiogenesis was assessed by counting microvessels in areas of maximal neovascularization after immunostaining with anti-factor VIII-related antigen antibodies in eight cases with proven homozygous deletion of the PTEN gene and 24 control cases. There was a statistically significant correlation between PTEN inactivation and increased microvessel counts. The microvessel density was higher at all Gleason scores in the cases with PTEN inactivation compared with control cases with the same score. To determine whether the increased angiogenesis in cases with PTEN inactivation was caused by downregulation of expression of the angiogenesis inhibitor thrombospondin-1, we analyzed a subset of the cases by immunostaining with anti-thrombospondin-1 antibody. Approximately 25% of cases showed decreased staining of prostate cancer cells, but there was no correlation with PTEN inactivation. Thus, PTEN inactivation is associated with increased angiogenesis, but the increased angiogenesis is not attributable to downregulation of thrombospondin-1 expression.
 ...
PMID:Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. 1020 63

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-regulation are (i) changing patterns of DNA methylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-alpha and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an important consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
Cancer Metastasis Rev
PMID:Epigenetic mechanisms for progression of prostate cancer. 1045 84

Loss of heterozygosity (LOH) in loci of the 10q23 region that harbor the PTEN gene and mutations in the sequence of this gene have been found in several primary human tumors including breast carcinomas, suggesting that this gene could be implicated in their pathogenesis. We investigated allelic losses in microsatellites of the 10q23 region, and their correlations with nine pathologic parameters in 105 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using five markers of the 10q23 region (D10S1687, D10S541, D10S2491, D10S583 and D10S571). LOH in at least one marker of the PTEN region was found in 29.5% of tumors. The statistical comparison between carcinomas with and without LOH in terms of the pathologic parameters showed significant differences in age (p = 0.03), lymph node metastases (p = 0.02), and higher histological grade (p = 0.02); a trend toward significance was found for progesterone receptors (p = 0.05). LOH in an individual marker and statistically significant relationships to tumor characteristics were observed at locus D10S541 for lymph node metastases (p = 0.04), at D10S2491 (intragenic to the PTEN gene) for lymph node metastases (p = 0.02), and at D10S583 for progesterone receptors (p = 0.01) and for high grade (p = 0.03). These results suggest the PTEN gene, or other genes of the 10q23 region, could be functionally related to breast cancer, probably influencing the development of histological features associated with poor prognosis.
 ...
PMID:Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. 1061

Malignant melanomas frequently show loss of alleles on the long arm of chromosome 10. The PTEN (MMAC1) gene has been identified as a tumour suppressor gene at 10q23.3 that is mutated in various types of advanced human cancers. We have investigated a series of 40 sporadic melanomas from 37 patients (15 primary cutaneous melanomas and 25 melanoma metastases) for allelic losses on chromosome 10, as well as for deletion and mutation of the PTEN gene. Microsatellite analysis revealed loss of heterozygosity at loci located on 10q in tumours from 15 of 34 patients investigated (44%). Somatic PTEN mutations were identified in melanomas from 4 of 37 patients (11%), all of whom had metastatic disease. In two of these patients, the tumours had additionally lost one PTEN allele, indicating complete loss of wild-type PTEN in the tumour cells. Our findings corroborate that loss of heterozygosity on chromosome 10 is a frequent aberration in malignant melanomas and implicate PTEN as a tumour suppressor gene inactivated by somatic mutation in a fraction of these tumours.
 ...
PMID:Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. 1088 43

A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.
 ...
PMID:Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. 1102 16

Extensive allelotyping studies have implicated several tumor-suppressor loci on chromosomes 3p, 5q, 6q, 8p, 9pq, 10q, 11q, 14q, 17p, 18q and 19p in human kidney tumorigenesis. The PTEN (also called MMAC1 and TEP1) gene, a candidate tumor suppressor located at chromosome 10q23.3, is mutated in a variety of sporadic malignancies as well as in patients with Cowden disease. To investigate the potential role of the PTEN gene in renal tumorigenesis, we searched for abnormalities of the gene in 68 primary renal-cell carcinomas (RCCs) as well as in 17 renal carcinoma-derived cell lines, using DNA-SSCP, sequencing and microsatellite analysis. Five of 68 (7.5%) primary RCCs exhibited intragenic mutations (3 missense, 1 deletion and 1 splice-site), and 1 of 17 (5.9%) cell lines had an insertion mutation. Loss of heterozygosity of the PTEN gene occurred in 25% of primary RCCs, including the 3 cases with intragenic mutation and the 1 PTEN-mutated cell line. Clinical and histopathological examinations revealed that 4 of the 5 primary tumors with PTEN mutation were high-grade, advanced clear-cell RCCs with distant metastases or renal vein tumor invasions, resulting in poor prognostic courses. The other was a low-stage papillary/chromophilic RCC. Our data suggest that PTEN mutation is observed in a subset of RCCs and that, especially in clear-cell RCCs, it occurs as a late-stage event and may contribute to the invasive and/or metastatic tumor phenotype.
 ...
PMID:PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. 1114 48


1 2 3 4 5 6 7 8 9 10 Next >>