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  • 1
    Abstract: Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P 〈 2.3 x 10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. SIGNIFICANCE: Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 25691096
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  • 2
    Publication Date: 2012-06-16
    Description: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez-Mancera, Pedro A -- Rust, Alistair G -- van der Weyden, Louise -- Kristiansen, Glen -- Li, Allen -- Sarver, Aaron L -- Silverstein, Kevin A T -- Grutzmann, Robert -- Aust, Daniela -- Rummele, Petra -- Knosel, Thomas -- Herd, Colin -- Stemple, Derek L -- Kettleborough, Ross -- Brosnan, Jacqueline A -- Li, Ang -- Morgan, Richard -- Knight, Spencer -- Yu, Jun -- Stegeman, Shane -- Collier, Lara S -- ten Hoeve, Jelle J -- de Ridder, Jeroen -- Klein, Alison P -- Goggins, Michael -- Hruban, Ralph H -- Chang, David K -- Biankin, Andrew V -- Grimmond, Sean M -- Australian Pancreatic Cancer Genome Initiative -- Wessels, Lodewyk F A -- Wood, Stephen A -- Iacobuzio-Donahue, Christine A -- Pilarsky, Christian -- Largaespada, David A -- Adams, David J -- Tuveson, David A -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA122183/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- K01 CA122183/CA/NCI NIH HHS/ -- K01 CA122183-05/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50CA62924/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoikis/genetics ; Carcinoma, Pancreatic Ductal/*enzymology/genetics/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Endopeptidases ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/*enzymology/genetics/pathology ; U937 Cells ; Ubiquitin Thiolesterase/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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