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

The long arm of chromosome 10 is frequently affected by allelic loss in prostate cancer. PTEN/MMAC1, a candidate tumor suppressor gene located at 10q23.3, a region commonly deleted in prostate cancer, was recently identified and found to be deleted or mutated in cancer cell lines derived from a variety of human tissues including prostate. To examine the role of PTEN/MMAC1 in the progression of prostate cancer, we screened a unique set of 50 metastatic prostate cancer tissues from 19 cancer-death patients for alterations in the PTEN/MMAC1 gene, using single-strand conformational polymorphism analysis and direct sequencing to identify sequence changes and microsatellite analysis to examine allelic loss in the vicinity of PTEN/MMAC1. Overall, gene alterations (deletions or point mutations) were observed in at least 1 metastatic site in 12 of the 19 patients studied. Two cases had homozygous deletions that were confirmed by fluorescence in situ hybridization analysis. Four patients harbored point mutations, with one mutation being found in all four tumors (a primary lesion and three different metastases) from the same patient. The remaining three mutations were detected in only one of multiple metastases. Loss of heterozygosity was found in 10 of 18 informative cases, with 1 case showing a unique pattern of microsatellite instability in each of six different metastases examined. Loss of the same allele was found in all metastases in a given patient in 9 of 10 cases. These results indicate that PTEN/MMAC1 gene alterations occur frequently in lethal prostate cancer, although a substantial amount of mutational heterogeneity is found among different metastatic sites within the same patient. These latter findings emphasize the potentially complex genetic relationship that can exist between various clonal lineages of prostate cancer cells as they evolve during the metastatic process and suggest a molecular basis for phenotypic heterogeneity of different prostate cancer foci in patients with disseminated disease.
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PMID:Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. 944 92

The genetic mechanisms underlying the progression to the metastatic phenotype of lung cancer are poorly understood. We recently showed that small cell lung cancer (SCLC) and metastasizing squamous cell carcinomas are characterized by an increased incidence of allelic loss on chromosome 10q. In the present study we performed a deletion mapping using 24 polymorphic markers on chromosome 10q22-q26 in 39 squamous cell carcinomas (SCC) of the lung identifying 14 metastatic carcinomas (74%) and three non-metastatic SCC (15%) with allelic imbalance. The allelotype analysis indicated three regions of allelic loss that were clustered at the loci Afm086/D10S541, D10S185 and D10S1782/D10S169. A localized microsatellite instability was observed in two carcinomas for the markers D10S1686 and D10S1782. In addition the PTEN/MMAC1 gene was analysed by direct DNA sequencing and Southern blot analysis in 25 and 28 carcinomas, respectively, without detecting any genomic alterations. Similarly, no altered transcript was detected in 15 tumor cell lines and 20 primary tumors by Northern blot analysis or RT-PCR. In summary, three distinct regions of allelic imbalance were identified suggesting that multiple tumor suppressor genes on chromosome 10q contribute to tumor progression and metastases formation of lung cancer.
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PMID:Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung. 969 38

We studied PTEN/MMAC1, a newly discovered candidate tumor suppressor gene at 10q23.3, for mutations in lung cancer. One hundred and thirty-six lung cancer cell line DNAs (66 small cell lung cancers, SCLC, 61 non-small cell lung cancers, NSCLC, four mesotheliomas, five extrapulmonary small cell cancers) were analysed for PTEN/MMAC1 homozygous deletions and five (8%) SCLC lines showed homozygous deletions interrupting the PTEN/MMAC1 gene. Using single stranded conformation polymorphism (SSCP) analysis, we screened the PTEN/MMAC1 open reading frame of 53 lung cancer cell line cDNAs for point mutations and found that 3/35 SCLCs and 3/18 NSCLCs contained homozygous amino acid sequence altering mutations. Northern blot analysis revealed that expression of the PTEN/MMAC1 gene was considerably lower in all the tumor cell lines with point mutations while no expression was detected for cell lines with PTEN/MMAC1 homozygous deletions. Mutation analysis of 22 uncultured, microdissected, primary SCLC tumors and metastases showed two silent mutations, and two apparent homozygous deletions. We also discovered a processed pseudogene (PTEN2) which has 98.5% nt identity to PTEN/MMAC1, that needs to be accounted for in cDNA mutation analysis. Our findings suggest that genetic abnormalities of the PTEN/MMAC1 gene are only involved in a relatively small subset of lung cancers.
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PMID:Mutation analysis of the PTEN/MMAC1 gene in lung cancer. 979 33

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.
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PMID:Loss of heterozygosity and mutational analysis of the PTEN/MMAC1 gene in synchronous endometrial and ovarian carcinomas. 1077 94

The high mutation rate in advanced brain tumors, recent functional studies, and the high frequency of mutations in prostate metastases all strongly suggest that PTEN/MMAC1 alterations are involved in the formation of metastases. We searched for genetic alterations in the PTEN/MMAC1 gene in 56 consecutive brain metastases from various primary tumors by loss of heterozygosity (LOH), direct sequence analysis, and differential PCR analysis. The highest LOH rates were detected in metastases deriving from lung (67%) and breast (64%) cancers. Three (25%) of the eight detected inactivating mutations (one nonsense mutation, one splice-site mutation, one 11-bp deletion, and five homozygous deletions) were found in metastases originating from 12 different lung carcinomas, suggesting that PTEN/MMAC1 alterations may play a role in the progression of this tumor. With the exception of lung carcinomas, our findings indicate that genetic abnormalities of the PTENM/MMAC1 gene are only involved in a relatively small subset of brain metastases. However, the discrepancy between the high overall LOH rate (50%) and the low frequency of PTEN/MMAC1 mutation detection rate (14%) suggests the presence of one or more additional tumor suppressor genes on chromosome 10q.
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PMID:Genetic alterations of the tumor suppressor gene PTEN/MMAC1 in human brain metastases. 1049 15

PTEN/MMAC1 is a putative tumor suppressor gene located on 10q23, one of the most frequently deleted chromosomal regions in human prostate cancer. Although mutations of PTEN have often been detected in metastases of prostate cancer, localized tumors have shown lower rates of mutation, which have varied from 0 to 20% among different studies. It is unknown whether the rate of PTEN mutations is different in prostate cancer from Asian men compared with Western men. To further clarify the role of PTEN in prostate cancer and to examine the gene for mutations in Asian men, we analyzed 32 cases of primary prostate cancers from Chinese patients, each of whom was not diagnosed by screening with serum prostate-specific antigen, for PTEN mutations using the methods of tissue microdissection, single-strand conformational polymorphism, and direct DNA sequencing. Seventy % of the tumors were Gleason scores 8-10, whereas the remainder were Gleason score 7. Six metastases of prostate cancer from American patients were also analyzed. Five of 32 (16%) primary prostate cancers from Chinese men and two of six metastases from American men showed mutations in a total of 10 codons of PTEN, which involved exons 1, 2, 5, 8, and 9. Two of the mutations were truncation type, whereas the rest were missense mutations. The mutation frequency in these cases from Asian patients was higher than that in our previous study of cases in radical prostatectomy specimens from American men, in which the 40 primary tumors were lower grade and had been detected by serum prostate-specific antigen test. We conclude that mutation of PTEN occurs more often in primary prostate cancers of Chinese men, whose tumors are high grade and reflective of an unscreened population.
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PMID:Mutations of PTEN/MMAC1 in primary prostate cancers from Chinese patients. 1123 84

A novel tumor suppressor gene, PTEN/MMAC1, on 10q23, displayed a number of mutations in solid tumors as gliomas and breast cancer. Aberrations of the long arm of chromosome 10 have been frequently detected in tumor progression of malignant melanoma of the skin by a variety of methods including cytogenetic analysis, fluorescence in situ hybridization and loss of heterozygosity analysis. Compared to previous studies, which propose an involvement of PTEN/MMAC1 in malignant melanoma mostly on the basis of data derived from cell lines and metastases, we analyzed a broader spectrum of exclusively patient derived tumor tissue by PCR and direct sequencing analysis of PTEN/MMAC1. Here, we present data of 25 primary melanomas (8 superficial spreading melanomas, 17 nodular melanomas) and 25 metastases of 41 patients. Neither loss of the complete gene nor a whole exon nor any nonsense mutations could be demonstrated. However, we detected several polymorphisms and some mutations in the introns, and in two metastatic tumors mutations with an amino acid change. Our results obtained from tissue samples underline that mutations of PTEN/MMAC1 are not an essential event in the onset of malignant melanoma of the skin, but could have an impact on tumor progression.
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PMID:PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. 1129 63

Recent advancement in the research of malignant melanoma is reviewed. Among many gene alterations detected in human melanoma, defect of CDKN2A located at chromosome 9p21 seems to be most important in the earlier developmental phase, though significance of this gene in the evolution of melanoma in situ has not been confirmed yet. Deletions of PTEN/MMAC1 on 10q23.3 and AIM1 on 6q21 as well as mutations of ras gene are involved in the later progression stages of melanoma. Adhesion molecules relevant to development and progression of melanoma have been intensely investigated in recent years, revealing crucial roles of cadherins and alpha(v)beta(3) integrin in the biologic behaviors of melanoma cells. Melanoma is characterized by extremely high potential of developing metastases. Dynamic changes of matrix metalloproteinase activity during invasion and movement of melanoma cells may be a major concern in this field. Fragility of blood vessels in melanoma lesions is another important point related to hematogeneous metastases. Acral lentiginous melanoma is a unique subtype of melanoma, because, in contrast to other subtypes, ultraviolet irradiation is not a major factor in its development. Investigation of pathogenesis of acral lentiginous melanoma surely provides us with new information about mechanism of melanocyte transformation. Recent advances in the management of malignant melanoma are also briefly reviewed, such as biochemotherapy, immunotherapy, and gene therapy. Finally, the concept of molecular classification of melanoma by gene expression profile is introduced, which possibly enables us to give the tailor-made therapy for each melanoma patient in the near future.
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PMID:Recent advances in melanoma research. 1132 15

PTEN/MMAC1/TEP1 (PTEN) is a tumor suppressor gene that is mutated in a variety of advanced and metastatic cancers, strongly suggests that PTEN alteration is possibly involved in the tumor progression and formation of metastases. However, the roles of PTEN in tumor growth and metastasis and its functional mechanisms are not fully understood. We evaluated the tumor suppressor function of PTEN gene on tumor growth and metastasis in vitro and in vivo. Our results of in vitro soft agar assay and in vivo PTEN-expressing tumor cell growth showed that PTEN inhibited the tumorigenicity of B16F10 melanoma cells. Anti-metastatic function of PTEN was also revealed by experimental pulmonary metastatic animal model. For the further insight into the mechanisms underlying the PTEN-mediated inhibition of tumor metastasis, we have examined the role of PTEN on the secretion of matrix metalloproteinases (MMPs), insulin-like growth factors (IGFs) and the expression of secretory and cellular vascular endothelial growth factor (VEGF) proteins that have been described to contribute to the metastasis of tumor. PTEN significantly lowered MMPs and IGFs secretion and also expression of secretory and cellular VEGF proteins. These results suggest that PTEN tumor suppressor protein inhibits tumorigenicity and metastasis through regulation of MMP, IGFs, and VEGF expression.
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PMID:Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. 1159 33

PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semi-quantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.
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PMID:PTEN/MMAC1 expression in melanoma resection specimens. 1245 73


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