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Increased Copy Number (increased + copy_number)
Selected AbstractsThe immunosuppressive drug leflunomide affects mating-pheromone response and sporulation by different mechanisms in Saccharomyces cerevisiaeFEMS MICROBIOLOGY LETTERS, Issue 1 2000Hiro-aki Fujimura Abstract Leflunomide (LFM) is a novel anti-inflammatory and immunosuppressive drug, and inhibits the growth of cytokine-stimulated lymphoid cells in vitro. The effect of LFM on haploid and diploid cells of Saccharomyces cerevisiae was investigated to elucidate the molecular mechanism of action of the drug. Using a halo assay, LFM was shown to enhance the cell cycle arrest of haploid cells induced by mating pheromone ,-factor. LFM also inhibited sporulation of diploid cells completely. S. cerevisiae genes which were cloned to suppress the anti-proliferative effect when present in increased copy number were introduced and examined for their activity to suppress the effect of LFM. Out of them, MLF4/SSH4, was found to suppress the sporulation-inhibitory effect of LFM. However, MLF4 failed to suppress the enhancing effect of LFM on pheromone response. Thus, LFM is suggested to act on haploid and diploid cells by different mechanisms. [source] The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancerGENES, CHROMOSOMES AND CANCER, Issue 7 2006Outi R. Saramäki Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) has been found in several malignancies, including prostate cancer, with an aggressive phenotype. Amplification of the gene has previously been demonstrated in several malignancies, but not in prostate cancer. Our goal was to evaluate the gene copy number and expression alterations of EZH2 in prostate cancer. The copy number of EZH2 in cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (n = 10), and clinical tumors (n = 191) was studied with fluorescence in situ hybridization. All cell lines had a gain of EZH2. Eight of the ten xenografts showed an increased copy number of the gene, including one case of high-level amplification (,5 copies of the gene and EZH2/centromere ratio ,2). 34/125 (27%) of untreated prostate carcinomas showed increased copy number, but only one case of low-level amplification (,5 copies of the gene and EZH2/centromere ratio <2), whereas half (25/46) of the hormone-refractory carcinomas showed increased copy number, including seven cases of low-level amplification and three cases of high-level amplification (P < 0.0001). Expression of EZH2 was significantly (P = 0.0009) higher in hormone-refractory prostate cancer compared with that in benign prostatic hyperplasia or untreated cancer, according to quantitative real-time RT-PCR assay. Also, the expression of EZH2 protein was found to be higher in hormone-refractory tumors than in hormone-naïve tumors by immunohistochemistry. The EZH2 gene amplification was significantly (P < 0.05) associated with increased EZH2 protein expression. The data show that amplification of the EZH2 gene is rare in early prostate cancer, whereas a fraction of late-stage tumors contains the gene amplification leading to the overexpression of the gene, thus indicating the importance of EZH2 in the progression of prostate cancer. © 2006 Wiley-Liss, Inc. [source] Allelic Gain and Amplification on the Long Arm of Chromosome 17 in Anaplastic MeningiomasBRAIN PATHOLOGY, Issue 2 2002Rainer Büschges Using comparative genomic hybridization (CGH) we have previously identified amplification at 17q21-qter as a common aberration in anaplastic meningiomas but not in atypical or benign meningiomas (19). To define the amplified genomic region, we analyzed 44 meningeal tumors, including 7 benign meningiomas of World Health Organization (WHO) grade I, 19 atypical meningiomas (WHO grade II) and 18 anaplastic meningiomas (WHO grade III) at 46 chromosome 17 loci (including 42 17q loci). In line with the CGH data we found evidence of increased numbers of alleles on 17q. The incidence rose with malignancy grade, culminating at 61% (11 of 18 cases) in the anaplastic meningioma group. The majority of cases showing increased allele numbers had, on average, low-level allelic gains (relative increase in allele dosage of 2- to 5-fold). Amplification of alleles (defined here as an average relative increase in allele dosage of more than 5 times) was detected in 2 anaplastic meningiomas. The amplification patterns in these tumors defined a number of common regions of amplification/increased allele copy number, the best defined include one between D17S790 and D17S1607 and one between D17S1160 and PS6K. Real-time PCR analysis of the PS6K candidate gene revealed no high-level amplification despite this affecting adjacent loci. Our findings are fundamental for the identification of the gene(s) in 17q22-q23 that is (are) the target(s) for increased copy number in anaplastic meningiomas and possibly other tumor types. [source] COPS3 amplification and clinical outcome in osteosarcomaCANCER, Issue 9 2007Taiqiang Yan MD Abstract BACKGROUND. Amplification of several genes that map to a region of chromosome 17p11.2, including COPS3, was observed in high-grade osteosarcoma. These genes were also shown to be overexpressed and may be involved in osteosarcoma tumorigenesis. COPS3 encodes a subunit of the COP9 signalosome implicated in the ubiquitination and ultimately degradation of the P53 tumor suppressor. To determine the relation between COPS3 amplification, P53 mutation, and patient outcome in osteosarcoma, tumors from a large cohort of patients with high-grade osteosarcoma and long-term clinical follow-up were examined. METHODS. Quantitative real-time polymerase chain reaction (PCR) was performed to detect copy number changes for COPS3, as well as additional genes (NCOR1, TOM1L2, and PMP22) from the 17p11.2 amplicon, in 155 osteosarcomas from a prospective collection of tumors with corresponding clinical data. Univariate and multivariate analyses were performed to assess differences in survival between groups. RESULTS. Amplification of COPS3, detected in 31% of the osteosarcomas, was strongly associated with large tumor size (P = .0009), but was not associated with age at diagnosis, site, sex, and tumor necrosis. COPS3 amplification was significantly correlated with a shorter time to metastasis with an estimated hazard ratio (HR) of 1.61 (95% confidence interval [CI], 1.02,2.55) in univariate analysis (log-rank test, P = .042). However, in an a priori multivariate Cox model including the other clinical parameters, the HR for COPS3 amplification decreased to 1.32 (95% CI, 0.82,2.13, P = .25), mainly due to the strong correlation with tumor size. COPS3 amplification and P53 mutation frequently occurred in the same tumors, suggesting that these are not mutually exclusive events in osteosarcoma. Although not statistically significant, patients whose tumors exhibited both molecular alterations tended to be more likely to develop metastasis compared with patients with either COPS3 amplification or P53 mutation alone. CONCLUSIONS. COPS3 is the likely target of the 17p11.2 amplicon. COPS3 may function as an oncogene in osteosarcoma, and an increased copy number may lead to an unfavorable prognosis. Cancer 2007. © 2007 American Cancer Society. [source] | ||||||||||