Publications
144 results found
Syed N, 2012, Polo Like Kinase 2 Tumour Suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in ovarian cancer, Oncotarget, Vol: 3, Pages: 78-83, ISSN: 1949-2553
The polo-like kinase PLK2 has recently been identified as a potential theranostic marker in the management of chemotherapy sensitive cancers. The methylation status of the PLK2 CpG island varies with sensitivity to paclitaxel and platinum in ovarian cancer cell lines. Importantly, extrapolation of these in vitro data to the clinical setting confirms that the methylation status of the PLK2 CpG island predicts outcomes in patients treated with carboplatin & paclitaxel chemotherapy. A second cell cycle regulator, p57Kip2, is also subject to epigenetic silencing in carboplatin resistance in vitro and in vivo, emphasising that cell cycle regulators are important determinants of sensitivity to chemotherapeutic agents and providing insights into the phenomenon of collateral drug sensitivity in oncology. Understanding the mechanistic basis and identification of robust biomarkers to predict collateral sensitivity may inform optimal use of chemotherapy in patients receiving multiple lines of treatment.
Lo Nigro C, Vivenza D, Monteverde M, et al., 2012, High frequency of complex TP53 mutations in CNS metastases from breast cancer, British Journal of Cancer, Vol: 106, Pages: 397-404, ISSN: 0007-0920
BACKGROUND: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 maycontribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-functionproperties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastrointestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervoussystem (CNS) metastatic breast cancer is not known.METHODS: In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres.RESULTS: We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation ofcomplex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breastcancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealedevidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breastcarcinoma to brain metastasis.CONCLUSION: Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cance
Lo Nigro C, Syed N, Lattanzio L, et al., 2011, The Prolyl-3-hydroxylases (P3H) and P3H-related Genes CRTAP and SC65 Are Novel Transcriptionally Silenced Genes in Burkitt's Lymphoma, European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Publisher: ELSEVIER SCI LTD, Pages: S107-S107, ISSN: 0959-8049
Benetatos L, Crook T, 2011, Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions, Annals of Hematology
Gasco M, Vivenza D, Monteverde M, et al., 2011, MDM2 309 single nucleotide polymorphisms (SNP) and clinical outcome in patients with advanced squamous cell carcinoma of head and neck (SCCHN)., J Clin Oncol, Vol: 29
5509 Background: Disruptive TP53 alterations have been associated with decreased survival in patients with SCCHN. A T>G polymorphism in the promoter region of mouse double minute 2 homologue (MDM2) has been associated with higher MDM2mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition. We hypothesized that the MDM2genotypes containing the G allele (GT+ GGgenotype) may be associated with worse survival in SCCHN patients (pts). METHODS: We directly sequenced the MDM2 polymorphism on both strands. We then evaluated the correlations between MDM2 polymorphism status and overall survival (OS) in 58 pts with stage III and IV SCCHN. Median follow-up was 6.5 years. All pts received cisplatin-based chemo-radiotherapy in our Department from 1997 to 2007. The Kaplan-Meier method and log-rank test were used to compare survival according to MDM2polymorphism status. Cox proportional hazards model was used to calculate hazard ratio (HR) adjusted for possible confounding variables, with 95% confidence interval (95% CI). RESULTS: Median age was 56 years; 50 pts (86%) were male and 52 pts (90%) were stage IV. The genotype frequencies for the MDM2 polymorphism were: T/T 32 (55%), T/G 17 (30%), G/G 9 (15%). Median overall survival (OS) and 5-years survival rates were significantly shorter in patients with genotypes containing the G allele (GT + GG genotype) compared to those with TT genotype (63 months vs. 124 months; log- rank p = 0.006 and 10/26 vs. 27/32; Fisher's exact p = 0.02, respectively). Notably, after adjusting for age, stage and performance status, genotypes containing the G allele appeared to be associated with worse survival (HR for death 2.90; 95% CI 1.37-6.12; p = 0.005). CONCLUSIONS: Our findings support the hypothesis that MDM2SNP309 polymorphism is an independent survival determinant among advanced stage SCCHN patients treated with cisplatin-based chemo-radiotherapy.
Gasco M, Vivenza D, Monteverde M, et al., 2011, MDM2 309 single nucleotide polymorphisms (SNP) and clinical outcome in patients with advanced squamous cell carcinoma of head and neck (SCCHN)., JOURNAL OF CLINICAL ONCOLOGY, Vol: 29, ISSN: 0732-183X
Lo Nigro C, Lattanzio L, Monteverde M, et al., 2011, The frequency of methylation of the NT5E gene in metastatic breast cancer., J Clin Oncol, Vol: 29
e11553 Background: Ecto-5-prime-nucleotidase (NT5E; CD73) catalyzes the conversion of purine 5-prime mononucleotides to nucleosides, the preferred substrate being AMP. Deficiency of NT5 occurs in a variety of immunodeficiency diseases and some studies have associated over-expression of NT5E with clinically aggressive neoplastic disease. Here we describe transcriptional down-regulation of the NT5E gene in breast cancer and show that this is associated with aberrant methylation in the CpG island located in its 5' regulatory sequences. METHODS: Methylation in the NT5E CpG island was analysed by methylation specific PCR (MSP) and quantitative pyrosequencing in a panel of 10 breast carcinoma cell lines and two independent clinical series of breast carcinomas, comprising 80 and 140 cases respectively and 17 brain metastatic breast cancer lesions. The breast carcinomas were predominantly invasive ductal carcinomas, untreated at the time of surgery and randomly selected from our clinical practice. Expression was assessed by qRT-PCR. RESULTS: NT5E mRNA was down-regulated in 4/10 breast carcinoma cell lines analysed. Down-regulation was associated with aberrant methylation in the CpG island located in the 5' regulatory sequences of the NT5E gene: methylation was present only in cell lines with down-regulation and the CpG island was unmethylated in cell lines which express the gene. Moreover, expression of NT5E was up-regulated by azacytidine. In clinical cases, methylation (assessed by pyrosequencing and/or MSP) was present in 28% and 41% of cases in independent clinical series of primary carcinomas. Methylation was more common in primary cases which ultimately relapsed at distant metastatic sites. Strikingly, methylation was particularly common in 9/16 brain metastatic lesions. CONCLUSIONS: In contrast to previous reports, we show that methylation of NT5E is common in metastatic breast cancer, particularly in intra-cranial metastases. Our data implicate transcriptional silen
Lo Nigro C, Lattanzio L, Monteverde M, et al., 2011, The frequency of methylation of the <i>NT5E</i> gene in metastatic breast cancer, JOURNAL OF CLINICAL ONCOLOGY, Vol: 29, ISSN: 0732-183X
Syed N, Crook T, 2011, Polo-like kinase Plk2 is an epigenetic determinant of chemosensitivity and clinical outcomes in ovarian cancer, Cancer Research
Syed N, O'Neilli K, Hughes M, et al., 2011, Transcriptional silencing disrupts two levels of arginine biosynthesis in glioblastoma multiforme: a novel, targeted therapeutic strategy for high grade gliomas, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Allen M, Syed N, Luong F, et al., 2011, Epigenetic silencing of argininosuccinate synthetase renders human bladder cancer cells sensitive to pegylated arginine deiminase, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Lo Nigro C, Gasco M, Vivenza D, et al., 2011, Genetic and epigenetic determinants of outcome in locally advanced head-and-neck cancer, CANCER RESEARCH, Vol: 71, ISSN: 0008-5472
Syed N, 2011, Transcriptional silencing disprupts two levels of arginine biosynthesis in glioblastoma multiforme: a novel targeted therapeutic strategy for high grade gliomas, AACR 102nd Annual Meeting
Syed N, 2011, The arginine biosynthetic pathway is targeted at two levels in glioblastoma multiforme brain tumours by epigenetic changes in arginino-succinate (ASS1) and arginino-succinate lyase (ASL):implications for targeted therapy, Journal of Clinical Investigation
Hatzmichael E, Bourantas K, 2010, Study of specific genetic and epigenetic variables in multiple myeloma., Leukemia and Lymphoma
Lo Nigro C, Syed N, Lattanzio L, et al., 2010, P3H COLLAGEN PROLYL HYDROXYLASES ARE TISSUE SELECTIVE TUMOUR SUPPRESSORS, 35th European-Society-for-Medical-Oncology (ESMO) Congress, Publisher: OXFORD UNIV PRESS, Pages: 42-43, ISSN: 0923-7534
Hannigan A, Inman G, 2010, Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter, The Journal of Clinical Investigation
Lee S, syed N, Taylor J, et al., 2010, DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma, British Journal of Cancer, Vol: 103
BACKGROUNDThe mitogen-activated protein kinase (MAPK) phosphatases or dual specificity phosphatases (DUSPs) are a family of proteins that catalyse the inactivation of MAPK in eukaryotic cells. Little is known of the expression, regulation or function of the DUSPs in human neoplasia.METHODSWe used RT-PCR and quantitative PCR (qPCR) to examine the expression of DUSP16 mRNA. The methylation in the DUSP16 CpG island was analysed using bisulphite sequencing and methylation-specific PCR. The activation of MAPK was determined using western blotting with phospho-specific antibodies for extra-cellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK). The proliferation of cell lines was assessed using the CellTiter 96 Aqueous One assay.RESULTSThe expression of DUSP16, which inactivates MAPK, is subject to methylation-dependent transcriptional silencing in Burkitt's Lymphoma (BL) cell lines and in primary BL. The silencing is associated with aberrant methylation in the CpG island in the 5' regulatory sequences of the gene blocking its constitutive expression. In contrast to BL, the CpG island of DUSP16 is unmethylated in other non-Hodgkin's lymphomas (NHLs) and epithelial malignancies. In BL cell lines, neither constitutive nor inducible ERK or p38 activity varied significantly with DUSP16 status. However, activation of JNK was increased in lines with DUSP16 methylation. Furthermore, methylation in the DUSP16 CpG island blocked transcriptional induction of DUSP16, thereby abrogating a normal physiological negative feedback loop that limits JNK activity, and conferred increased cellular sensitivity to agents, such as sorbitol and anthracycline chemotherapeutic agents that activate JNK.CONCLUSIONDUSP16 is a new epigenetically regulated determinant of JNK activation in BL.
Lee S, Syed N, Taylor J, et al., 2010, DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma, British Journal of Cancer, Vol: 103, Pages: 265-274, ISSN: 1532-1827
Schmid P, Fleischmann C, Wischnewsky M, et al., 2010, Use of prolyl 3-hydroxylases (P3H) to predict endocrine sensitivity in primary breast cancer., JOURNAL OF CLINICAL ONCOLOGY, Vol: 28, ISSN: 0732-183X
Hatzimichael E, Crook T, 2010, The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia, European Journal of Haematology
Hatzimichael E, Dasoula A, Shah R, et al., 2010, The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia, EUROPEAN JOURNAL OF HAEMATOLOGY, Vol: 84, Pages: 47-51, ISSN: 0902-4441
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- Citations: 37
Syed N, 2009, Deficiency of argininosuccinate synthetase expression confers sensitivity to arginine depletion with arginine deiminase in glioblastomas, AACR: Genetics and Biology of Brain Cancers
Despite aggressive radio-chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor. New agents are therefore required. The molecular mechanisms, which are key in the pathogenesis and progression of GBM are still poorly understood. A recent documented mutations of isocitrate dehydrogenase 1 and 2 in more than 70% of astrocytomas (Yah H, 2009) brought the attention on metabolism as a primary target in the development of novel treatment modalities for these tumours. Using de novo gene finding techniques and epigenetic profiling in human GBM cell lines and cultured explants of primary GBM, we observed frequent transcriptional silencing of the 2 most important enzymes of the arginine biosynthetic pathway: argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL). We observed that loss of expression of ASS1, as determined by RT-PCR and immunohistochemistry, confers arginine auxotrophy to GBM cell lines and primary tumour explants. This confers sensitivity to highly selective, dose-dependent killing of the cells by arginine deprivation due to either nutritional starvation or pharmacological depletion with pegylated arginine deiminase (ADI-PEG20, Polaris Pharmaceuticals, Inc., San Diego, CA, USA). We have further demonstrated on tumour tissue sections that 20% of de novo GBMs have little or no expression of ASS1 indicating that ASS1 expression tested by immunohistochemistry represents an excellent predictor of response to arginine deprivation with arginine deiminase treatment. These pharmacogenomic findings suggest that ASS1 negativity may serve as a biomarker to select a population sensitive to arginine depletion with ADI-PEG20. Further studies are warranted.
Dasoula A, Hatzimichael E, Dranitsaris G, et al., 2009, Snk/Plk2 CpG methylation in patients with multiple myeloma, 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Bower M, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts, 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Bower M, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high-grade B lymphoma cell lines and novel epigenetic changes conserved between immunocompetent and HIV-positive hosts., J Clin Oncol, Vol: 27
8585 Background: Methylation-dependent transcriptional silencing is an important mechanism of tumour suppressor gene inactivation in neoplasia, including lymphoma. METHODS: Pharmacological "unmasking" of transcriptionally silenced genes in B lymphoma cell lines was achieved using 5' deazacytidine ± Trichostatin A and subsequent analysis of mRNA levels on micro-array. Candidate genes thus identified, were further analysed by qPCR, methylation-specific PCR (MSP) and bisulphite sequencing in B lymphoma cell lines and by MSP in clinical samples from sporadic (immunocompetent) (18 cases) and HIV-infected patients (14 cases). Samples in both patient groups were diffuse large B cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). Additionally, we analysed 8 cases of marginal zone lymphoma (MZL) from the immunocompetent group. RESULTS: We report the identification of 13 novel genes, not previously described in the literature, which are subject to methylation-dependent transcriptional silencing in high-grade lymphoma and whose expression can be reactivated by demethylating agents. The novel genes encode proteins involved in diverse functional classes and include pro-apoptotic members of the p53 pathway (Scotin), transcriptional regulators (Baz2B) and regulators of telomerase (Smrf2). The frequency of methylation in individual genes varied from approximately 10% to 75% in specific lymphoma subtypes, but was in general similar in high grade lymphomas in immunocompetent and HIV-infected hosts. CONCLUSIONS: Using pharmacological reversal of methylation, we have identified a number of genes, not previously implicated in human neoplasia, which are subject to transcriptional silencing in high-grade B lymphomas. The similar frequencies of methylation, observed in immunocompetent and HIV positive patients implies that the genes are fundamental in suppression of lymphomagenesis. Detection of methylated DNA of one or more of these genes may have utility as biomarkers of
Dasoula A, Hatzimichael E, Dranitsaris G, et al., 2009, Snk/Plk2 CpG methylation in patients with multiple myeloma., J Clin Oncol, Vol: 27
e19532 Background: We previously showed that polo like kinase 2 (Snk/Plk2) is subject to methylation-dependent transcriptional silencing in a very high frequency in Burkitt lymphomas. Here, we have examined CpG methylation in Snk/Plk2 in a well-characterized series of multiple myeloma (MM) patients. METHODS: Bone marrow samples from individuals with MM were obtained at diagnosis and in 5 cases at disease progression as well. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits. The methylation-specific polymerase chain reaction (MSP) was employed to study its methylation status. Control methylated and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals proven to have no haematological malignancy, served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and the development of advanced disease (DS≥II), extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels. RESULTS: We analyzed the methylation of Snk/Plk2 in 45 cases of MM (24 male, 21 female, mean age 66.4 years ±12.4). Classical cytogenetic analysis was available in 30/45 patients and none of them was found to have chromosome 13 abnormalities. No sample from the control population was found methylated. The Snk/Plk2 promoter was found to be methylated in 27/45 patients (60%). Median survival of patients in whom the Snk/Plk2 CpG island was methylated was 7.1 years compared to a median survival of 8.8 years for unmethylated. However Snk/Plk2 methylation was not a predictor of excess mortality (HR=0.6, p=0.5), bone lytic lesions (OR=0.56, p=0.3), anemia (OR=0.5, p=0.3) or advanced stage as defined above (OR=0.8, p=0.7). CONCLUSIONS: Snk/Plk2 DNA Methylation is a frequent event in patients with multiple myeloma. There was no association between the methylation status of the gene and relevant clinical par
Crook T, Syed N, Papoudou-Bai A, et al., 2009, Methylation reversal in high grade B lymphoma cell lines identifies novel epigenetic changes conserved between immunocompetent and HIV-positive hosts and others specific to HIV-associated lymphoma, HIV MEDICINE, Vol: 10, Pages: 5-5, ISSN: 1464-2662
Benetatos L, Bourantas KL, 2008, Methylation analysis of the von Hippel-Lindau gene in acute myeloid leukaemia and myelodysplastic syndromes, Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Lim SL, Green JA, 2008, Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer, British Journal of Cancer
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