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Differential Gene Expression in the Peripheral Zone Compared to the Transition Zone of the Human Prostate Gland

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Prostate Cancer and Prostatic Diseases (2008) 11, 173–180 & 2008 Nature Publishing Group All rights reserved 1365-7852/08 $30.00 www.nature.com/pcan ORIGINAL ARTICLE Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland EE Noel1,4, N Ragavan2,3,4, MJ Walsh2, SY James1, SS Matanhelia3, CM Nicholson3, Y-J Lu1 and FL Martin2 1Medical Oncology Centre, Institute of Cancer, Barts and London School of Medicine and Dentistry Queen Mary, University of London, London, UK; 2Biomedical Sciences Unit, Department of Biological Sciences, Lancaster University, Lancaster, UK and 3Lancashire Teaching Hospitals NHS Trust, Preston, UK Gene expression profiles may lend insight into whether prostate adenocarcinoma (CaP) predominantly occurs in the peripheral zone (PZ) compared to the transition zone (TZ). From human prostates, tissue sets consisting of PZ and TZ were isolated to investigate whether there is a differential level of gene expression between these two regions of this gland. Gene expression profiling using Affymetrix Human Genome U133 plus 2.0 arrays coupled with quantitative real- time reverse transcriptase-PCR was employed. Genes associated with neurogenesis, signal transduction, embryo implantation and cell adhesion were found to be expressed at a higher level in the PZ. Those overexpressed in the TZ were associated with neurogenesis development, signal transduction, cell motility and development. Whether such differential gene expression profiles may identify molecular mechanisms responsible for susceptibility to CaP remains to be ascertained. Prostate Cancer and Prostatic Diseases (2008) 11, 173–180; doi:10.1038/sj.pcan.4500997; published online 24 July 2007 Keywords: differential expression; oligonucleotide microarrays; prostate adenocarcinoma; peripheral zone; quantitative real-time RT-PCR; transition zone Introduction PZ- and TZ-derived stem cells5 or expression of hormone-metabolising enzymes (for example, CYP1B1)6 The human prostate is conventionally divided into regions have been suggested factors in this morphological or tightly fused zones known as the peripheral zone (PZ), susceptibility. The CZ may have a different embryogenic the central zone (CZ) and the transition zone (TZ).1 The origin (that is, the mesonepheric duct; the urogenital multifocal entity of prostate adenocarcinoma (CaP) arises sinus is believed to give rise to the PZ and TZ1) and mostly in the PZ whereas the non-malignant overgrowth consistent with this, its protein profile differs from that of of benign prostatic hypertrophy occurs exclusively in the the other zones.7 Paradoxically, PZ and TZ glandular TZ; the CZ seems to be relatively immune to both epithelia were found to express similar protein profiles7 pathologies.1 CaP is the most common male cancer in and have a similar proliferative index and incidence of Europe, North America and some parts of Africa,2 and apoptosis.8 Following analysis by Fourier-transform epidemiological studies of populations that migrated from infrared microspectroscopy, TZ epithelium was unex- low- to high-risk regions point to dietary and/or lifestyle pectedly found to be more likely to exhibit a suscept- factors playing an important role in its aetiology.3 ibility-to-adenocarcinoma spectral signature than PZ.9 CaP progression is a multistage process from latent If epithelial cells lining the branched tubuloacinar carcinoma(s) of low-histological grade to high-grade glands of the PZ and TZ are equally susceptible to metastatic disease.4 Whether this pathology is predomi- initiating events, other effects (for example, growth nantly PZ-associated remains to be ascertained but promotion by hormone-associated genes or the epige- divergent hormone responsiveness of primary putative netic silencing of protective genes) might give rise to CaP progression. To investigate this, we examined the differential gene expression profile of CaP-free tissue Correspondence: Dr FL Martin, Biomedical Sciences Unit, sets consisting of PZ and TZ. Employing oligonucleotide Department of Biological Sciences, Lancaster University, Lancaster microarrays and candidate gene verification using LA1 4YQ, UK. quantitative real-time reverse transcriptase (RT)-poly- E-mail: [email protected] 4These authors contributed equally to this study. merase chain reaction (PCR), our aim was to identify Received 22 January 2007; revised 7 May 2007; accepted 10 June 2007; genes whose zone-specific preferential expression might published online 24 July 2007 be associated with susceptibility or resistance to CaP. Differential gene expression in the human prostate EE Noel et al 174 Materials and methods RNA extraction Towards transcript profiling, total RNA was extracted Study participants using TRIzol reagent (Invitrogen, Paisley, UK) according Informed consent to obtain tissue for research was to the manufacturer’s instructions and purified by obtained (LREC no. 2003.6.v; Preston, Chorley and South ethanol precipitation to remove any residual reagents. Ribble Ethical Committee). Study participants were RNA concentration was quantified using the Nanodrop selected from patients undergoing radical retropubic ND-1000 spectrophotometer, and quality was assessed prostatectomy (RRP) for CaP on the basis of a low by observing the integrity of 28S and 18S bands using an prostate-specific antigen (o20 mg/l serum) and low Agilent 2100 Bioanalyzer (Agilent Technologies, Wald- volume of disease (p2 core biopsies positive for CaP bronn, Germany). For the purposes of this study, the per 8 taken). A further CaP-free tissue was obtained after samples were grouped by prostate zone. Samples (n ¼ 6) a radical cystoprostatectomy for removal of muscle- from three tissue sets (PZ and TZ per individual patient) invasive bladder carcinoma. were stored at À801C until use and contributed sepa- rately (that is, one sample per chip) towards three values per prostate region (Figures 1a and b). Tissue retrieval and storage Towards quantitative real-time RT-PCR, total RNA After surgical resection, prostate tissue was transported extraction was performed using the Qiagen RNeasy Kit to the pathology laboratory (o3 min) and dissected in combination with the Qiagen RNase-free DNase kit using aseptic techniques. Provisionally, tissue assumed (Qiagen Ltd). to be cancer-free was selected (from the lobe from which Based on experience, these two extraction methods biopsy cores were negative for cancer); formalin-fixed were conducted independently in different laboratories. sections stained with hematoxylin and eosin were However, the finding that both sets of analyses were checked retrospectively to assess whether CaP was likely confirmatory (see below) lends strong support to the to be absent. Using a forceps and scalpel, the prostate robustness of the datasets generated. tissue was sliced from the upper part of the gland starting just above the area of the verumontanum. The tissues (2 cm in length and 0.3 cm in width) isolated from Transcript profiling and data analysis the most peripheral and postero-lateral aspect of the A One Cycle Eukaryotic Target Labeling Assay (Affyme- gland were designated as PZ while the tissues (1.5 cm in trix, Santa Clara, CA, USA) was used for amplification length and 0.3 cm in width) isolated from the area and biotinylation of tissue-extracted RNA. Sample immediately lateral to the urethra (peri-urethral) were preparation and hybridization were carried out follow- designated as TZ. Tissue sets (PZ and TZ per individual ing the manufacturer’s instructions. Briefly, 5 mg of total patient) were immediately placed in RNAlater (Qiagen RNA was reverse transcribed using T7 promoter se- Ltd, Crawley, West Sussex, UK) and stored at À851C. quence-tagged random hexamers and the resulting Remaining prostate was formalin fixed for histopatho- double-stranded cDNA was used as a template to logy. generate biotin-labelled antisense cRNA by in vitro Tissue sets consisting of PZ and TZ were obtained transcription. After clean-up, 20 mg of full-length cRNA from 12 patients (53–69 years); 11 of these underwent was fragmented by metal-induced hydrolysis. The RRP while patient 12 had a cystoprostatectomy (Table 1). quality of the fragmented cRNA was verified on an On digital rectal examination, carried out by a single Agilent 2100 Bioanalyzer (Agilent Technologies). Sam- assessor, eight participants were characterized as benign ples were hybridized for 16 h at 451C on the Affymetrix (non-cancerous-feeling glands—stage T1c) and the re- Human Genome U133 plus 2.0 high-density microarray maining patients had a malignant-feeling gland in one containing 54 675 probes (that is, 24 325 Unigene clus- lobe (stage T2). A single pathologist assigned the Gleason ters). Following post-hybridization washes, the arrays grade; in one tissue (PZ of patient no. 4), a node of were scanned using the Affymetrix GeneChip Scanner malignancy was found following retrospective histo- 3000 7G and expression data were analysed using pathology. GeneSpring v7.2 software (Silicon Genetics, Redwood Table 1 Details of study participants and tissue samples examined Patient no. Age (years) PSA (mg/l) DRE Smoking status Alcohol Diet Gleason grade 1 54 4.6 T2 right lobe No Yes NV 4+3 2 68 4.4 Benign No Yes NV 3+4 3 58 4.6 Benign No Yes NV 3+3 4 53 19.1 T2 right lobe Yes Yes NV 4+3 5 53 8.1 T2 left lobe Yes Yes NV 3+3 6 67 8.1 Benign No Yes NV 3+4 7 68 6.9 Benign Yes Yes NV 3+4 8 69 8.0 Benign Yes Yes NV 3+3 9 67 6.2 T2 left lobe Yes Yes NV 4+3 10 60 5.4 Benign Yes Yes NV 3+3 11 59 4.4 Benign Yes Yes NV 3+4 12a 62 9.0 Benign Yes Yes NV NA Abbreviations: DRE, digital rectal examination; NA, not applicable; NV, non-vegetarian; PSA, prostate-specific antigen. Gleason grade given is in reference to CaP present in the lobe from which biopsy cores were positive for cancer. aAll patients had RRP except patient no. 12 who had cystoprostatectomy for removal of muscle-invasive bladder carcinoma.
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  • Convergent Functional Genomics of Schizophrenia: from Comprehensive Understanding to Genetic Risk Prediction

    Convergent Functional Genomics of Schizophrenia: from Comprehensive Understanding to Genetic Risk Prediction

    Molecular Psychiatry (2012) 17, 887 -- 905 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp IMMEDIATE COMMUNICATION Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction M Ayalew1,2,9, H Le-Niculescu1,9, DF Levey1, N Jain1, B Changala1, SD Patel1, E Winiger1, A Breier1, A Shekhar1, R Amdur3, D Koller4, JI Nurnberger1, A Corvin5, M Geyer6, MT Tsuang6, D Salomon7, NJ Schork7, AH Fanous3, MC O’Donovan8 and AB Niculescu1,2 We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-- coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease.