Publications by year
2017
Murphy TM, Crawford B, Dempster EL, Hannon E, Burrage J, Turecki G, Kaminsky Z, Mill J (2017). Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
Transl Psychiatry,
7(1).
Abstract:
Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.
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2016
McDermott E, Ryan EJ, Tosetto M, Gibson D, Burrage J, Keegan D, Byrne K, Crowe E, Sexton G, Malone K, et al (2016). DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis.
J Crohns Colitis,
10(1), 77-86.
Abstract:
DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis.
BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity. METHODS: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. RESULTS: a total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. CONCLUSIONS: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.
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Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, Troakes C, Turecki G, O'Donovan MC, Schalkwyk LC, et al (2016). Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
Nat Neurosci,
19(1), 48-54.
Abstract:
Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.
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2015
Murphy TM, O'Donovan A, Mullins N, O'Farrelly C, McCann A, Malone K (2015). Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes.
Psychiatr Genet,
25(2), 71-78.
Abstract:
Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes.
OBJECTIVES: Anxiety is associated with elevated levels of the inflammatory cytokine interleukin-6 (IL-6) and an increased risk for diseases with an inflammatory aetiology. In cancer, higher levels of IL-6 have been associated with increased expression of the epigenetic enzymes DNMT1 and Enhancer of Zeste Homolog 2 (EZH2). However, the relationship between IL-6 and DNA methyltransferases (DNMTs) and EZH2 expression has not previously been examined in anxious individuals. METHODS: Global DNA methylation levels were measured using the Methylflash Methylated DNA Quantification Kit and gene expression levels of the DNMT and EZH2 genes in anxious (n=25) and nonanxious individuals (n=22) were compared using quantitative real-time PCR. Specifically, we investigated whether global DNA methylation or aberrant expression of these genes was correlated with IL-6 mRNA and protein serum levels in anxious individuals. RESULTS: Anxious participants had significantly higher levels of global DNA methylation compared with controls (P=0.001). There were no differences in the mean mRNA expression levels of the DNMT1/3A/3B, EZH2 and IL-6 genes in anxious individuals compared with controls. However, the expression of DNMT1/3A, EZH2 and IL-6 genes increases with increasing Hospital Anxiety and Depression Scale-Anxiety scores in the anxious cohort only. Interestingly, IL-6 gene expression was correlated strongly with DNMT1/3A/3B and EZH2 expression, highlighting a potential relationship between IL-6 and important epigenetic regulatory enzymes. CONCLUSION: This study provides novel insight into the relationship between anxiety, epigenetics and IL-6. Moreover, our findings support the hypothesis that changes in DNA methylation profiles may contribute to the biology of anxiety.
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McDermott E, Murphy T, Sexton G, Keegan D, Doherty G, Cullen G, Mulcahy H, Ryan E (2015). Global DNA methylation in inflammatory bowel disease.
IRISH JOURNAL OF MEDICAL SCIENCE,
184, S24-S25.
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Fisher HL, Murphy TM, Arseneault L, Caspi A, Moffitt TE, Viana J, Hannon E, Pidsley R, Burrage J, Dempster EL, et al (2015). Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
Epigenetics,
10(11), 1014-1023.
Abstract:
Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age-12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems.
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Murphy TM, Wong CCY, Arseneault L, Burrage J, Macdonald R, Hannon E, Fisher HL, Ambler A, Moffitt TE, Caspi A, et al (2015). Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins.
Clin Epigenetics,
7Abstract:
Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins.
BACKGROUND: Asthma is the most common chronic inflammatory disorder in children. The aetiology of asthma pathology is complex and highly heterogeneous, involving the interplay between genetic and environmental risk factors that is hypothesized to involve epigenetic processes. Our aim was to explore whether methylomic variation in early childhood is associated with discordance for asthma symptoms within monozygotic (MZ) twin pairs recruited from the Environmental Risk (E-Risk) longitudinal twin study. We also aimed to identify differences in DNA methylation that are associated with asthma that develops in childhood and persists into early adulthood as these may represent useful prognostic biomarkers. RESULTS: We examined genome-wide patterns of DNA methylation in buccal cell samples collected from 37 MZ twin pairs discordant for asthma at age 10. DNA methylation at individual CpG sites demonstrated significant variability within discordant MZ twin pairs with the top-ranked nominally significant differentially methylated position (DMP) located in the HGSNAT gene. We stratified our analysis by assessing DNA methylation differences in a sub-group of MZ twin pairs who remained persistently discordant for asthma at age 18. The top-ranked nominally significant DMP associated with persisting asthma is located in the vicinity of the HLX gene, which has been previously implicated in childhood asthma. CONCLUSIONS: We identified DNA methylation differences associated with childhood asthma in peripheral DNA samples from discordant MZ twin pairs. Our data suggest that differences in DNA methylation associated with childhood asthma which persists into early adulthood are distinct from those associated with asthma which remits.
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Murphy TM, Tuzova AV, O Rourke CJ, O Meachair S, Greene C, Sullivan L, Thornhill J, Barrett C, Loftus B, Lynch T, et al (2015). Multigene methylation biomarker analysis in prostate cancer.
Epigenetic Diagnosis and Therapy,
1(1), 19-27.
Abstract:
Multigene methylation biomarker analysis in prostate cancer
© 2015 Bentham Science Publishers.Prostate cancer (PCa) is a leading cause of cancer-related death in men. Prostate specific antigen (PSA) screening has reduced PCa-related mortality but at the high price of over-detection of latent disease. Furthermore, PSA is marred by an unacceptably high false-positive rate. Thus, alternative biomarkers are required. Promoter hypermethylation at specific gene loci is known to be a prevalent oncogenic event in PCa. The aim of this study was to carry out an integrative, quantitative analysis of DNA methylation to determine a highly PCa-specific panel that could be used as a molecular correlate of adverse clinicopathologic features as an adjunct to PSA to improve the early detection of PCa. We examined methylation of 9 genes (APC, CDKN2A, DCR2, GSTP1, IGFBP3, IGFBP7, PTGS2, SFRP2 and TMS1) in combination, in PCa and control groups: tumor-adjacent histologically benign tissue (TAB) and benign prostatic hyperplasia (BPH), from men with no evidence of PCa. Using a previously reported analytic method, a methylation (M) score was calculated for each sample to predict the risk of PCa in individual subjects, by summing the log odds ratio for each gene analyzed by multivariate logistic regression analysis of tumor versus benign. Two multi-gene methylation panels (M_score(APC, GSTP1, IGFBP3) and M_score(APC, GSTP1)) were identified, which differentiated between PCa and TAB (sensitivity 91.1%; specificity 80%) or PCa and BPH (sensitivity 91%; specificity 85.9%), respectively. The high tumor-specificity of the M_score warrants further investigations into liquid samples of blood and urine to determine the sensitivity of this test for non-invasive detection of PCa.
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2014
Murphy TM, Mill J (2014). Epigenetics in health and disease: Heralding the EWAS era. The Lancet, 383(9933), 1952-1954.
Fisher H, Murphy T, Arseneault L, Burrage J, Dempster E, Caspi A, Moffitt T, Mill J (2014). Genome-wide DNA methylation profiling in monozygotic twins discordant for psychotic symptoms at age 12.
EARLY INTERVENTION IN PSYCHIATRY,
8, 57-57.
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McDermott E, Rowan C, Murphy T, Byrne K, Doherty G, Cullen G, Mulcahy H, Ryan E (2014). Global DNA methylation in inflammatory bowel disease.
JOURNAL OF CROHNS & COLITIS,
8, S342-S342.
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Davies MN, Krause L, Bell JT, Gao F, Ward KJ, Wu H, Lu H, Liu Y, Tsai P-C, Collier DA, et al (2014). Hypermethylation in the ZBTB20 gene is associated with major depressive disorder.
GENOME BIOLOGY,
15(4).
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2013
Perry AS, O'Hurley G, Raheem OA, Brennan K, Wong S, O'Grady A, Kennedy AM, Marignol L, Murphy TM, Sullivan L, et al (2013). Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.
Int J Cancer,
132(8), 1771-1780.
Abstract:
Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.
Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.
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Murphy TM, Mullins N, Ryan M, Foster T, Kelly C, McClelland R, O'Grady J, Corcoran E, Brady J, Reilly M, et al (2013). Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients.
Genes Brain Behav,
12(1), 125-132.
Abstract:
Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients.
Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3' UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.
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O'Rourke CJ, Murphy TM, Hollywood D, Perry AS (2013). Mining methylome databases.
Trends Genet,
29(2), 63-65.
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2012
Murphy TM, Mullins N, Foster T, Kelly C, McClelland R, O'Grady J, Corcoran E, Brady J, Reilly M, Jeffers A, et al (2012). A Functional Dnmt3b Polymorphism is Associated with Suicide Attempt in Psychiatric Patients.
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Sullivan L, Murphy TM, Barrett C, Loftus B, Thornhill J, Lawler M, Hollywood D, Lynch T, Perry AS (2012). IGFBP7 promoter methylation and gene expression analysis in prostate cancer.
J Urol,
188(4), 1354-1360.
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IGFBP7 promoter methylation and gene expression analysis in prostate cancer.
IGFBP7 belongs to a family of insulin-like growth factor-1 regulatory binding proteins. IGFBP7 hypermethylation is associated with its down-regulation in various carcinomas. In prostate cancer IGFBP7 down-regulation has been widely reported but to our knowledge the mechanisms behind this event are unknown. We performed a denaturing high performance liquid chromatography screening and validation strategy to profile the methylation status of IGFBP7 in prostate cancer.
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2011
Murphy TM, Sullivan L, Lane C, O'Connor L, Barrett C, Hollywood D, Lynch T, Lawler M, Perry AS (2011). In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.
Prostate,
71(1), 1-17.
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In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.
Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC).
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Murphy TM, Ryan M, Foster T, Kelly C, McClelland R, O'Grady J, Corcoran E, Brady J, Reilly M, Jeffers A, et al (2011). Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms.
Behav Brain Funct,
7Abstract:
Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms.
Suicidal behaviour is known to aggregate in families. Patients with psychiatric disorders are at higher risk for suicide attempts (SA), however protective and risk genetic variants for suicide appear to be independent of underlying psychiatric disorders. Here we investigate genetic variants in genes important for neurobiological pathways linked to suicidal behaviour and/or associated endophenotypes, for association with SA among patients with co-existing psychiatric illness. Selected gene-gene and gene-environment interactions were also tested.
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2008
Murphy TM, Perry AS, Lawler M (2008). The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer.
Endocr Relat Cancer,
15(1), 11-25.
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The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer.
It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype. A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many processes including apoptosis. To date, studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast, colon and stomach, with only limited data available on prostate cancer. Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer. The most significant advances have involved the discovery of apoptotic gene targets of methylation, including XAF1, (fragile histidine triad (FHIT ), cellular retinol binding protein 1 (CRBP1), decoy receptor 1(DCR1), decoy receptor 2 (DCR2 ), target of methylation-induced silenceing 1 (TMS1), TNF receptor superfamily, member 6 (FAS), Reprimo (RPRM) and GLI pathogenesis-related 1 (GLIPR1). These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers. We also introduce the concept of an 'apoptotic methylation signature' for prostate cancer and evaluate its potential in a diagnostic, prognostic and therapeutic setting.
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2007
Murphy TM, Perry AS, O'Connor L, Lawler M (2007). A bioinformatics approach to identify candidate apoptotic genes which may be the subject of epigenetic control in prostate cancer.
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