@article{be686851bc00455994517c64de9ce8a4,
title = "Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2: ERG fusion status",
abstract = "Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusionpositive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR=0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR=1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.",
author = "{The PRACTICAL consortium} and Manuel Luedeke and Rinckleb, {Antje E.} and FitzGerald, {Liesel M.} and Geybels, {Milan S.} and Johanna Schleutker and Eeles, {Rosalind A.} and Teixeira, {Manuel R.} and Lisa Cannon-Albright and Ostrander, {Elaine A.} and Steffen Weikert and Kathleen Herkommer and Tiina Wahlfors and Tapio Visakorpi and Leinonen, {Katri A.} and Tammela, {Teuvo L.J.} and Cooper, {Colin S.} and Zsofia Kote-Jarai and Sandra Edwards and Goh, {Chee L.} and Frank McCarthy and Chris Parker and Penny Flohr and Paula Paulo and Carmen Jer{\'o}nimo and Rui Henrique and Hans Krause and Sven Wach and Verena Lieb and Rau, {Tilman T.} and Walther Vogel and Rainer Kuefer and Hofer, {Matthias D.} and Sven Perner and Rubin, {Mark A.} and Agarwal, {Archana M.} and Easton, {Doug F.} and {Al Olama}, {Ali Amin} and Sara Benlloch and Josef Hoegel and Stanford, {Janet L.} and Christiane Maier",
note = "Funding Information: This study would not have been possible without the contributions of the following collaborators: Per Hall (COGS), Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissie' re and Frederic Robidoux and the staff of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Linda Enroth, Daniel Brewer, Michaela Eggel, Riitta Vaalavuo and Liisa M{\"a}{\"a}tt{\"a}nen are thanked for technical assistance and database maintenance. RAE acknowledges support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. ML was a fellow of the International Graduate School in Molecular Medicine, Ulm. AER was a fellow of the Heinrich Warner Foundation. The GTEx Consortium is acknowledged for the GTEx data (the full acknowledgement is available in the Supplementary Materials). This work was supported by the following grants for the iCOGS infrastructure: European Community's Seventh Framework Programme under grant agreement no 223175 [HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; the National Institutes of Health [CA128978] and Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112-the GAME-ON initiative]; the Department of Defence [W81XWH-10-1-0341]; the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; the Breast Cancer Research Foundation; and the Ovarian Cancer Research Fund. The FHCRC, Tampere, UKGPCS and Ulm groups are part of the ICPCG, supported by the National Institutes of Health [U01 CA089600]. The Molecular Prostate Cancer project of Ulm was funded by the Deutsche Krebshilfe. The Berlin and Ulm collaboration was supported by the Berliner Krebsgesellschaft. The FHCRC studies were supported by the U.S. National Cancer Institute, National Institutes of Health [RO1 CA056678, RO1 CA082664, RO1 CA092579]; with additional support from the Fred Hutchinson Cancer Research Center. Genotyping was supported by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health. The Tampere (Finland) study was supported by the Academy of Finland [116437, 251074, 126714]; the Finnish Cancer Organisations; Sigrid Juselius Foundation; and The Medical Research Fund of Tampere University Hospital [no. 9L091]. The PSA screening samples were collected by the Finnish part of ERSPC (European Study of Screening for Prostate Cancer). Funding to pay the Open Access publication charges for this article was provided by Cancer Research UK. Publisher Copyright: {\textcopyright} The Author 2016.",
year = "2016",
doi = "10.1093/hmg/ddw349",
language = "English (US)",
volume = "25",
pages = "5490--5499",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",
}
