ProfessorBobBrown

Thathia SH, Ferguson S, Gautrey HE, van Otterdijk SD, Hili M, Rand V, Moorman AV, Meyer S, Brown R, Strathdee Get al., 2012, Epigenetic inactivation of <i>TWIST2</i> in acute lymphoblastic leukemia modulates proliferation, cell survival and chemosensitivity, HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, Vol: 97, Pages: 371-378, ISSN: 0390-6078

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• Citations: 30

Kaye S, Brown R, Gabra H, Gore Met al., 2011, Preface, ISBN: 9781441972156

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Chapman-Rothe N, Brown R, 2011, Prospects for Epigenetic Compounds in the treatment of Human Disease, Epigenetic Contributions in Autoimmune Disease, Editors: Ballestar

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Cherblanc F, Lo Y-P, De Gussem E, Alcazar-Fuoli L, Bignell E, He Y, Chapman-Rothe N, Bultinck P, Herrebout WA, Brown R, Rzepa HS, Fuchter MJet al., 2011, On the Determination of the Stereochemistry of Semisynthetic Natural Product Analogues using Chiroptical Spectroscopy: Desulfurization of Epidithiodioxopiperazine Fungal Metabolites, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 17, Pages: 11868-11875, ISSN: 0947-6539

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• Citations: 27

Huang RS, Johnatty SE, Gamazon ER, Im HK, Ziliak D, Duan S, Zhang W, Kistner EO, Chen P, Beesley J, Mi S, O'Donnell PH, Fraiman YS, Das S, Cox NJ, Lu Y, MacGregor S, Goode EL, Vierkant RA, Fridley BL, Hogdall E, Kjaer SK, Jensen A, Moysich KB, Grasela M, Odunsi K, Brown R, Paul J, Lambrechts D, Despierre E, Vergote I, Gross J, Karlan BY, deFazio A, Chenevix-Trench G, Dolan MEet al., 2011, Platinum Sensitivity-Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 5490-5500, ISSN: 1078-0432

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• Citations: 49

Goode EL, Chenevix-Trench G, Hartmann LC, Fridley BL, Kalli KR, Vierkant RA, Larson MC, White KL, Keeney GL, Oberg TN, Cunningham JM, Beesley J, Johnatty SE, Chen X, Goodman KE, Armasu SM, Rider DN, Sicotte H, Schmidt MM, Elliott EA, Hogdall E, Kjaer SK, Fasching PA, Ekici AB, Lambrechts D, Despierre E, Hogdall C, Lundvall L, Karlan BY, Gross J, Brown R, Chien J, Duggan DJ, Tsai Y-Y, Phelan CM, Kelemen LE, Peethambaram PP, Schildkraut JM, Shridhar V, Sutphen R, Couch FJ, Sellers TAet al., 2011, Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 20, Pages: 1638-1648, ISSN: 1055-9965

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• Citations: 31

Stronach EA, Alfraidi A, Rama N, Datler C, Studd JB, Agarwal R, Guney TG, Gourley C, Hennessy BT, Mills GB, Mai A, Brown R, Dina R, Gabra Het al., 2011, HDAC4-Regulated STAT1 Activation Mediates Platinum Resistance in Ovarian Cancer, CANCER RESEARCH, Vol: 71, Pages: 4412-4422, ISSN: 0008-5472

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• Citations: 135

Dai W, Teodoridis JM, Zeller C, Graham J, Hersey J, Flanagan JM, Stronach E, Millan DW, Siddiqui N, Paul J, Brown Ret al., 2011, Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 4052-4062, ISSN: 1078-0432

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• Citations: 77

Pharoah PDP, Palmieri RT, Ramus SJ, Gayther SA, Andrulis IL, Anton-Culver H, Antonenkova N, Antoniou AC, Goldgar D, Beattie MS, Beckmann MW, Birrer MJ, Bogdanova N, Bolton KL, Brewster W, Brooks-Wilson A, Brown R, Butzow R, Caldes T, Caligo MA, Campbell I, Chang-Claude J, Chen YA, Cook LS, Couch FJ, Cramer DW, Cunningham JM, Despierre E, Doherty JA, Doerk T, Duerst M, Eccles DM, Ekici AB, Easton D, Fasching PA, de Fazio A, Fenstermacher DA, Flanagan JM, Fridley BL, Friedman E, Gao B, Sinilnikova O, Gentry-Maharaj A, Godwin AK, Goode EL, Goodman MT, Gross J, Hansen TVO, Harnett P, Rookus M, Heikkinen T, Hein R, Hogdall C, Hogdall E, Iversen ES, Jakubowska A, Johnatty SE, Karlan BY, Kauff ND, Kaye SB, Chenevix-Trench G, Kelemen LE, Kiemeney LA, Kjaer SK, Lambrechts D, LaPolla JP, Lazaro C, Le ND, Leminen A, Leunen K, Levine DA, Lu Y, Lundvall L, Macgregor S, Marees T, Massuger LF, McLaughlin JR, Menon U, Montagna M, Moysich KB, Narod SA, Nathanson KL, Nedergaard L, Ness RB, Nevanlinna H, Nickels S, Osorio A, Paul J, Pearce CL, Phelan CM, Pike MC, Radice P, Rossing MA, Schildkraut JM, Sellers TA, Singer CF, Song H, Stram DO, Sutphen R, Lindblom A, Terry KL, Tsai Y-Y, van Altena AM, Vergote I, Vierkant RA, Vitonis AF, Walsh C, Wang-Gohrke S, Wappenschmidt B, Wu AH, Ziogas A, Berchuck A, Risch HAet al., 2011, The Role of <i>KRAS</i> rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 3742-3750, ISSN: 1078-0432

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• Citations: 38

Steele NL, Plumb JA, Vidal L, Tjornelund J, Knoblauch P, Buhl-Jensen P, Molife R, Brown R, de Bono JS, Evans TRJet al., 2011, Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101), CANCER CHEMOTHERAPY AND PHARMACOLOGY, Vol: 67, Pages: 1273-1279, ISSN: 0344-5704

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• Citations: 44

Amankwah EK, Wang Q, Schildkraut JM, Tsai Y-Y, Ramus SJ, Fridley BL, Beesley J, Johnatty SE, Webb PM, Chenevix-Trench G, Dale LC, Lambrechts D, Amant F, Despierre E, Vergote I, Gayther SA, Gentry-Maharaj A, Menon U, Chang-Claude J, Wang-Gohrke S, Anton-Culver H, Ziogas A, Doerk T, Duerst M, Antonenkova N, Bogdanova N, Brown R, Flanagan JM, Kaye SB, Paul J, Butzow R, Nevanlinna H, Campbell I, Eccles DM, Karlan BY, Gross J, Walsh C, Pharoah PDP, Song H, Kjaer SK, Hogdall E, Hogdall C, Lundvall L, Nedergaard L, Kiemeney LALM, Massuger LFAG, van Altena AM, Vermeulen SHHM, Le ND, Brooks-Wilson A, Cook LS, Phelan CM, Cunningham JM, Vachon CM, Vierkant RA, Iversen ES, Berchuck A, Goode EL, Sellers TA, Kelemen LEet al., 2011, Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium, PLOS One, Vol: 6, ISSN: 1932-6203

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (Pheterogeneity≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; Ptrend = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (Pheterogeneity≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; Ptrend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (Pheterogeneity≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (Pinteraction≤0.003), age at diagnosis (Pinteraction = 0.04), and year of diagnosis (Pinteraction = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

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Sriraksa R, Zeller C, El-Bahrawy MA, Dai W, Daduang J, Jearanaikoon P, Chau-in S, Brown R, Limpaiboon Tet al., 2011, CpG-island methylation study of liver fluke-related cholangiocarcinoma, British Journal of Cancer, Vol: 104, Pages: 1313-1318, ISSN: 0007-0920

Background:Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers.Methods:We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry.Results:A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1.Conclusion:Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP.

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Rizzo S, Hersey JM, Mellor P, Dai W, Santos-Silva A, Liber D, Luk L, Titley I, Carden CP, Box G, Hudson DL, Kaye SB, Brown Ret al., 2011, Ovarian Cancer Stem Cell-Like Side Populations Are Enriched Following Chemotherapy and Overexpress <i>EZH2</i>, MOLECULAR CANCER THERAPEUTICS, Vol: 10, Pages: 325-335, ISSN: 1535-7163

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• Citations: 168

He Y, Wood SJ, Paul J, Motsinger-Reif A, Auman T, Hoskins JM, Brown R, McLeod HLet al., 2011, GENETIC MARKERS ASSOCIATED WITH PLATINUM/TAXANES INDUCED GASTROINTESTINAL TOXICITY IN SCOTROC1 TRIAL, 112th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics, Publisher: NATURE PUBLISHING GROUP, Pages: S4-S5, ISSN: 0009-9236

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He Y, Wood SJ, Paul J, Motsinger-Reif A, Auman T, Hoskins JM, Brown R, McLeod HLet al., 2011, GENETIC MARKERS ASSOCIATED WITH PLATINUM/TAXANES INDUCED GASTROINTESTINAL TOXICITY IN SCOTROC1 TRIAL., 112th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics, Publisher: NATURE PUBLISHING GROUP, Pages: S66-S67, ISSN: 0009-9236

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• Citations: 1

Chapman-Rothe N, Brown R, 2011, PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE, EPIGENETIC CONTRIBUTIONS IN AUTOIMMUNE DISEASE, Vol: 711, Pages: 150-161, ISSN: 0065-2598

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• Citations: 1

Kaye S, Brown R, Gabra H, Gore Met al., 2010, Emerging Therapeutic Targets in Ovarian Cancer, Publisher: Springer Verlag, ISBN: 9781441972156

This book offers a progress report on efforts to meet the challenges faced by ovarian cancer patients and their doctors.

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McKay S, Unger K, Sriraksa R, Zeller C, Pericleous S, Spalding D, Thomas Get al., 2010, Differing copy number alteration profiles identified by array CGH in Thai Intrahepatic Cholangiocarcinoma related to prognosis., London 4th Surgical Symposium

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Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M, Jones C, Sher T, Gentry-Maharaj A, Wozniak E, Tsai Y-Y, Weidhaas J, Paik D, Van den Berg DJ, Stram DO, Pearce CL, Wu AH, Brewster W, Anton-Culver H, Ziogas A, Narod SA, Levine DA, Kaye SB, Brown R, Paul J, Flanagan J, Sieh W, McGuire V, Whittemore AS, Campbell I, Gore ME, Lissowska J, Yang HP, Medrek K, Gronwald J, Lubinski J, Jakubowska A, Le ND, Cook LS, Kelemen LE, Brook-Wilson A, Massuger LFAG, Kiemeney LA, Aben KKH, van Altena AM, Houlston R, Tomlinson I, Palmieri RT, Moorman PG, Schildkraut J, Iversen ES, Phelan C, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Kruger-Kjaer S, Blaeker J, Hogdall E, Hogdall C, Gross J, Karlan BY, Ness RB, Edwards RP, Odunsi K, Moyisch KB, Baker JA, Modugno F, Heikkinenen T, Butzow R, Nevanlinna H, Leminen A, Bogdanova N, Antonenkova N, Doerk T, Hillemanns P, Duerst M, Runnebaum I, Thompson PJ, Carney ME, Goodman MT, Lurie G, Wang-Gohrke S, Hein R, Chang-Claude J, Rossing MA, Cushing-Haugen KL, Doherty J, Chen C, Rafnar T, Besenbacher S, Sulem P, Stefansson K, Birrer MJ, Terry KL, Hernandez D, Cramer DW, Vergote I, Amant F, Lambrechts D, Despierre E, Fasching PA, Beckmann MW, Thiel FC, Ekici AB, Chen X, Johnatty SE, Webb PM, Beesley J, Chanock S, Garcia-Closas M, Sellers T, Easton DF, Berchuck A, Chenevix-Trench G, Pharoah PDP, Gayther SAet al., 2010, Common variants at 19p13 are associated with susceptibility to ovarian cancer, Nature Genetics, Vol: 42, Pages: 880-884, ISSN: 1546-1718

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10−4 and P = 6 × 10−4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10−9 and P = 4 × 10−11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

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Zeller C, Brown R, 2010, Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer, Therapeutic Advances in Medical Oncology, Vol: 2, Pages: 319-329

Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance.

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Strathdee G, Ferguson S, Sim A, Brown Ret al., 2010, DNA methylation does not regulate JUNB expression in CML: Comment on "Downregulation of JUNB mRNA expression in advanced phase chronic myelogenous leukemia" by Hoshino et al. [Leuk. Res. 33 (2009) 1361-1366], LEUKEMIA RESEARCH, Vol: 34, Pages: 685-686, ISSN: 0145-2126

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Paige AJW, Zucknick M, Janczar S, Paul J, Mein CA, Taylor KJ, Stewart M, Gourley C, Richardson S, Perren T, Ganesan TS, Smyth JF, Brown R, Gabra Het al., 2010, <i>WWOX</i> tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis, EUROPEAN JOURNAL OF CANCER, Vol: 46, Pages: 818-825, ISSN: 0959-8049

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• Citations: 24

Chapman-Rothe N, Brown R, 2009, “Approaches to target the genome and its epigenome in cancer”, Future Medicinal Chemistry, Vol: 1, Pages: 1481-1495

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Chapman-Rothe N, Brown R, 2009, Approaches to target the genome and its epigenome in cancer., Future Med Chem, Vol: 1, Pages: 1481-1495

The term epigenetic landscape was coined by CH Waddington to describe how cell fates were established in development, visualized as valleys and ridges directing the irreversibility of cell type differentiation. It is now clear that normal differentiation control breaks down during tumor development and that all tumor types show aberrant regulation of the epigenetic code, including changes in DNA methylation, histone modification and microRNAs. This has led to much interest in the development of epigenetic cancer therapies to target this aberrant epigenetic regulation. Histone deacetylase and DNA methyltransferase inhibitors are now used in the treatment of certain hematological malignancies. However, their more general applicability to solid tumors may be limited by lack of specificity and delivery challenges. Approaches to overcome these limitations and how to develop more specific drugs are discussed. The use of RNAi in the context of genome regulation as well as the possibility to use polyamides and engineered zinc fingers to target master regulators in the future is examined. Ultimately, improved specificity of epigenetic therapies will require increased mapping of the aberrant epigenetic landscape in cancer and cancer-specific target validation using chemical epigenetic approaches.

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Huang Y-W, Jansen RA, Fabbri E, Potter D, Liyanarachchi S, Chan MWY, Liu JC, Crijns APG, Brown R, Nephew KP, Van Der Zee AGJ, Cohn DE, Yan PS, Huang TH-M, Lin H-JLet al., 2009, Identification of candidate epigenetic biomarkers for ovarian cancer detection, ONCOLOGY REPORTS, Vol: 22, Pages: 853-861, ISSN: 1021-335X

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• Citations: 37

Scott LC, Evans TRJ, Cassidy J, Harden S, Paul J, Ullah R, O'Brien V, Brown Ret al., 2009, Cytokeratin 18 in plasma of patients with gastrointestinal adenocarcinoma as a biomarker of tumour response, BRITISH JOURNAL OF CANCER, Vol: 101, Pages: 410-417, ISSN: 0007-0920

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• Citations: 44

Graham JS, Kaye SB, Brown R, 2009, The promises and pitfalls of epigenetic therapies in solid tumours, EUROPEAN JOURNAL OF CANCER, Vol: 45, Pages: 1129-1136, ISSN: 0959-8049

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• Citations: 76

Steele N, Finn P, Brown R, Plumb JAet al., 2009, Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo, British Journal of Cancer, Vol: 100, Pages: 758-763, ISSN: 0007-0920

Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing.

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Paige AJW, Brown R, 2008, Pharmaco(epi)genomics in ovarian cancer, PHARMACOGENOMICS, Vol: 9, Pages: 1825-1834, ISSN: 1462-2416

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• Citations: 18

Johnatty SE, Beesley J, Paul J, Fereday S, Spurdle AB, Webb PM, Byth K, Marsh S, McLeod H, Harnett PR, Brown R, de Fazio A, Chenevix-Trench Get al., 2008, <i>ABCB1</i> (<i>MDR 1</i>) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy, CLINICAL CANCER RESEARCH, Vol: 14, Pages: 5594-5601, ISSN: 1078-0432

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• Citations: 84