A large-scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

Shane Stegeman, Ernest Amankwah, Kerenaftali Klein, Trace A O'Mara, Donghwa Kim, Hui Yi Lin, Jennifer Permuth-Wey, Thomas A. Sellers, Srilakshmi Srinivasan, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Fik Wiklund, Henrik Gronberg, Christopher A. Haiman, Johanna SchleutkerBørge G. Nordestgaard, Ruth C. Travis, David Neal, Paul Pharoah, Kay Tee Khaw, Janet L. Stanford, William J. Blot, Stephen Thibodeau, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Radka Kaneva, Manuel R. Teixeira, Amanda B. Spurdle, Judith A. Clements, Jong Y. Park, Jyotsna Batra, Margaret Cook, Angela Morgan, Artitaya Lophatananon, Cyril Fisher, Daniel Leongamornlert, Edward J. Saunders, Emma J. Sawyer, Koveela Govindasami, Malgorzata Tymrakiewicz, Michelle Guy, Naomi Livni, Rosemary Wilkinson, Sara Jugurnauth-Little, Steve Hazel, Tokhir Dadaev, John Pedersen, John L. Hopper, Melissa C. Southey, Ami Karlsson, Carin Cavalli-Bjoerkman, Jan Erik Johansson, Jan Adolfson, Markus Aly, Michael Broms, Paer Stattin, Brian E. Henderson, Fredrick Schumacher, Anssi Auvinen, Kimmo Taari, Liisa Maeaettaenen, Paula Kujala, Teemu Murtola, Teuvo L.J. Tammela, Tiina Wahlfors, Andreas Roder, Peter Iversen, Peter Klarskov, Sune F. Nielsen, Maren Weischer, Tim J. Key, Hans Wallinder, Sven Gustafsson, Jenny L. Donovan, Freddie Hamdy, Anne George, Athene Lane, Gemma Marsden, Michael Davis, Paul Brown, Nora Pashayan, Sarah Holt, Lisa B. Signorello, Wei Zheng, Liang Wang, Lori Tillmans, Shaun Riska, Antje Rinckleb, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Dominika Wokozorczyk, Jan Lubiski, Wojciech Kluzniak, Aida K. Dieffenbach, Christa Stegmaier, Volker Arndt, Babu Zachariah, Hyun Park, Julio Pow-Sang, Maria Rincon, Selina Radlein, Aleksandrina Vlahova, Atanaska Mitkova, Chavdar Slavov, Darina Kachakova, Elenko Popov, Svetlana Christova, Tihomir Dikov, Vanio Mitev, Felicity Lose, Joana Santos, Joao Barros-Silva, Paula Paulo, Pedro Pinto, Rui Henrique, Sofia Maia, Gail Risbridger, Renea Taylor, Wayne Tilley, Lisa Butler, Lisa Horvath, Trina Yeadon, Allison Eckert, Glen Wood, Peter Heathcote, Greg Malone, Kris Kerr, Megan Turner, Angus Collins

Tutkimustuotos: ArtikkeliTieteellinenvertaisarvioitu

54 Sitaatiot (Scopus)

Abstrakti

<p>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 × 10<sup>-5</sup>) 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.</p>
AlkuperäiskieliEnglanti
Sivut368-379
Sivumäärä12
JulkaisuCANCER DISCOVERY
Vuosikerta5
Numero4
DOI - pysyväislinkit
TilaJulkaistu - 2015
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

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