Larkin SE, Holmes S, Cree IA et al.Identification of markers of prostate cancer progression using candidate gene expression. Br J Cancer 106:157-165

School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michaels Building, White Swan Road, Portsmouth, PO1 2DT, UK.
British Journal of Cancer (Impact Factor: 4.84). 11/2011; 106(1):157-65. DOI: 10.1038/bjc.2011.490
Source: PubMed


Metastatic prostate cancer (PCa) has no curative treatment options. Some forms of PCa are indolent and slow growing, while others metastasise quickly and may prove fatal within a very short time. The basis of this variable prognosis is poorly understood, despite considerable research. The aim of this study was to identify markers associated with the progression of PCa.
Artificial neuronal network analysis combined with data from literature and previous work produced a panel of putative PCa progression markers, which were used in a transcriptomic analysis of 29 radical prostatectomy samples and correlated with clinical outcome.
Statistical analysis yielded seven putative markers of PCa progression, ANPEP, ABL1, PSCA, EFNA1, HSPB1, INMT and TRIP13. Two data transformation methods were utilised with only markers that were significant in both selected for further analysis. ANPEP and EFNA1 were significantly correlated with Gleason score. Models of progression co-utilising markers ANPEP and ABL1 or ANPEP and PSCA had the ability to correctly predict indolent or aggressive disease, based on Gleason score, in 89.7% and 86.2% of cases, respectively. Another model of TRIP13 expression in combination with preoperative PSA level and Gleason score was able to correctly predict recurrence in 85.7% of cases.
This proof of principle study demonstrates a novel association of carcinogenic and tumourigenic gene expression with PCa stage and prognosis.


Available from: Paul A Townsend
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    • "Little is known about how the individual signature genes influence prostate cancer progression. Upregulation of some genes or their encoded protein has been associated with aggressive disease (BIRC5, MCM2 and TRIP13) (Shariat et al, 2004; Larkin et al, 2012; Toubaji et al, 2012). Moreover, SCD has been shown to enhance AR transcriptional activity and thereby promote proliferation of prostate cancer cells (Kim et al, 2011), FOXM1 seems to have a role in prostate carcinogenesis (Chandran et al, 2007; Cai et al, 2013) and transcriptional upregulation of the AR target ZWINT has been associated with castration-resistant prostate cancer (Urbanucci et al, 2012). "
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    ABSTRACT: Background: The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer. Methods: Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two independent cohorts of 59 and 281 patients were used for validation. Results: Expression of genes in proliferation, DNA repair and hypoxia response was a major part of the transcriptional programme associated with pimonidazole staining. A signature of 32 essential genes was constructed and showed positive correlation to Ki67 staining, confirming the increased proliferation in hypoxic tumours as suggested from the gene data. Positive correlations were also found to tumour stage and lymph node status, but not to blood prostate-specific antigen level, consistent with the findings for pimonidazole staining. The association with aggressiveness was confirmed in validation cohorts, where the signature correlated with Gleason score and had independent prognostic impact, respectively. Conclusions: Pimonidazole staining reflects an aggressive hypoxic phenotype of prostate cancer characterised by upregulation of proliferation, DNA repair and hypoxia response genes.
    British Journal of Cancer 12/2014; 112(2). DOI:10.1038/bjc.2014.604 · 4.84 Impact Factor
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    • "Here, we hypothesized that if our candidate disease-associated genes can successfully distinguish cancer samples from control samples in these tested datasets, they can be further shown to be related to prostate cancer and regarded as a potential module biomarker. Moreover, we compared our results with those obtained with a public biomarker set for prostate cancer [64], which were derived from differential gene expression. Five-fold cross validation was used to assess the performance based on different biomarkers and the SVM regression was used as the classifier. "
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    ABSTRACT: Background Prostate cancer is one of the most common complex diseases with high leading cause of death in men. Identifications of prostate cancer associated genes and biomarkers are thus essential as they can gain insights into the mechanisms underlying disease progression and advancing for early diagnosis and developing effective therapies. Methods In this study, we presented an integrative analysis of gene expression profiling and protein interaction network at a systematic level to reveal candidate disease-associated genes and biomarkers for prostate cancer progression. At first, we reconstructed the human prostate cancer protein-protein interaction network (HPC-PPIN) and the network was then integrated with the prostate cancer gene expression data to identify modules related to different phases in prostate cancer. At last, the candidate module biomarkers were validated by its predictive ability of prostate cancer progression. Results Different phases-specific modules were identified for prostate cancer. Among these modules, transcription Androgen Receptor (AR) nuclear signaling and Epidermal Growth Factor Receptor (EGFR) signalling pathway were shown to be the pathway targets for prostate cancer progression. The identified candidate disease-associated genes showed better predictive ability of prostate cancer progression than those of published biomarkers. In context of functional enrichment analysis, interestingly candidate disease-associated genes were enriched in the nucleus and different functions were encoded for potential transcription factors, for examples key players as AR, Myc, ESR1 and hidden player as Sp1 which was considered as a potential novel biomarker for prostate cancer. Conclusions The successful results on prostate cancer samples demonstrated that the integrative analysis is powerful and useful approach to detect candidate disease-associate genes and modules which can be used as the potential biomarkers for prostate cancer progression. The data, tools and supplementary files for this integrative analysis are deposited at
    BMC Medical Genomics 05/2014; 7(Suppl 1):S3. DOI:10.1186/1755-8794-7-S1-S3 · 2.87 Impact Factor
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    • "In hepatocellular carcinoma (HCC), EFNA1 mRNA was overexpressed compared with adjacent nontumorous tissues, and the level of secreted EFNA1 in serum samples from HCC patients were significantly higher than those from healthy controls (Cui et al., 2010). Likewise, elevated expression of EFNA1 was observed in gastric cancer (Nakamura et al., 2005), bladder cancer (Abraham et al., 2006) and more recently, prostate cancer (Larkin et al., 2012). "
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    ABSTRACT: Accumulated evidence has indicated that Ephrin A1 (EFNA1) is associated with angiogenesis and tumorigenesis in various types of malignancies, including colorectal cancer (CRC). In the current study, we performed an online search using the public microarray database to investigate whether EFNA1 expression might be altered in CRC tissues. We then conducted a case-control study including 306 subjects (102 cases and 204 well-matched controls) in Xiaoshan County to assess any association between genetic polymorphisms in EFNA1 and CRC susceptibility. Searches in the Oncomine expression profiling database revealed EFNA1 to be overexpressed in CRC tissue compared with adjacent normal tissue. The rs12904 G-A variant located in the 3' untranslated region (UTR) of EFNA1 was observed to be associated with CRC susceptibility. Compared with the AA homozygous genotype, those carrying GA genotype had a decreased risk of developing CRC (odds ratio (OR) =0.469, 95% confidence interval (CI): 0.225-0.977, and P =0.043). The association was stronger among smokers and tea drinkers, however, no statistical evidence of interaction between rs12904 polymorphism and smoking or tea drinking on CRC risk was found. Our results suggest that EFNA1 is involved in colorectal tumorigenesis, and rs12904 A>G polymorphism in the 3' UTR of EFNA1 is associated with CRC susceptibility. Larger studies and further mechanistic investigations are warranted to confirm our findings.
    Asian Pacific journal of cancer prevention: APJCP 09/2013; 14(9):5037-41. DOI:10.7314/APJCP.2013.14.9.5037 · 2.51 Impact Factor
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