Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status

Luedeke M, Rinckleb AE, Fitzgerald LM, Geybels MS, Schleutker J, Eeles RA, Teixeira MR, Cannon-Albright L, Ostrander EA, Weikert S, Herkommer K, Wahlfors T, Visakorpi T, Leinonen KA, Tammela TLJ, Cooper CS, Kote-Jarai Z, Edwards S, Goh CL, Mccarthy F, Parker C, Flohr P, Paulo P, Jeronimo C, Henrique R, Krause H, Wach S, Lieb V, Rau T, Vogel W, Kuefer R, Hofer MD, Perner S, Rubin MA, Agarwal AM, Easton DF, Al Olama AA, Benlloch S, Hoegel J, Stanford JL, Maier C (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 25

Pages Range: 5490-5499

Journal Issue: 24

DOI: 10.1093/hmg/ddw349

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 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.

Involved external institutions

Universidade do Porto Portugal (PT) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universität Ulm Germany (DE) Fred Hutchinson Cancer Research Center Canada (CA) University of Cambridge United Kingdom (GB) University of Utah United States (USA) (US) Cornell University United States (USA) (US) Northwestern University United States (USA) (US) Alb Fils Kliniken Germany (DE) Vivantes - Netzwerk für Gesundheit GmbH Germany (DE) Instituto Português de Oncologia Francisco Gentil (IPO) / Portuguese Oncology Institute Portugal (PT) The Institute of Cancer Research (ICR) United Kingdom (GB) Royal Marsden Hospital / The Royal Marsden NHS Foundation Trust United Kingdom (GB) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) University of Tampere (UTA) / Tampereen yliopisto (Tay) Finland (FI) Technische Universität München (TUM) Germany (DE) National Human Genome Research Institute (NHGRI) United States (USA) (US)

How to cite

APA:

Luedeke, M., Rinckleb, A.E., Fitzgerald, L.M., Geybels, M.S., Schleutker, J., Eeles, R.A.,... Maier, C. (2016). Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Human Molecular Genetics, 25(24), 5490-5499. https://doi.org/10.1093/hmg/ddw349

MLA:

Luedeke, Manuel, et al. "Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status." Human Molecular Genetics 25.24 (2016): 5490-5499.

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