A1 Refereed original research article in a scientific journal
Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status
Authors: Manuel Luedeke, Antje E. Rinckleb, Liesel M. FitzGerald, Milan S. Geybels, Johanna Schleutker, Rosalind A. Eeles, Manuel R. Teixeira, Lisa Cannon-Albright, Elaine A. Ostrander, Steffen Weikert, Kathleen Herkommer, Tiina Wahlfors, Tapio Visakorpi, Katri A. Leinonen, Teuvo L.J. Tammela, Colin S. Cooper, Zsofia Kote-Jarai, Sandra Edwards, Chee L. Goh, Frank McCarthy, Chris Parker, Penny Flohr, Paula Paulo, Carmen Jerónimo, Rui Henrique, Hans Krause, Sven Wach, Verena Lieb, Tilman T. Rau, Walther Vogel, Rainer Kuefer, Matthias D. Hofer, Sven Perner, Mark A. Rubin, Archana M. Agarwal, Doug F. Easton, Ali Amin Al Olama, Sara Benlloch, The PRACTICAL consortium, Josef Hoegel, Janet L. Stanford, Christiane Maier
Publisher: OXFORD UNIV PRESS
Publication year: 2016
Journal: Human Molecular Genetics
Journal name in source: HUMAN MOLECULAR GENETICS
Journal acronym: HUM MOL GENET
Volume: 25
Issue: 24
First page : 5490
Last page: 5499
Number of pages: 10
ISSN: 0964-6906
DOI: https://doi.org/10.1093/hmg/ddw349
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 fusion-positive 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.
