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 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.
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.|Department of Urology, University of Ulm, Ulm, Germany.
authors: Manuel
authors: M
authors: Luedeke
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.|Department of Urology, University of Ulm, Ulm, Germany.
authors: Antje E
authors: AE
authors: Rinckleb
authors: Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, Washington, USA.|Cancer, Genetics and Immunology, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Liesel M
authors: LM
authors: FitzGerald
authors: Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, Washington, USA.
authors: Milan S
authors: MS
authors: Geybels
authors: Institute of Biomedical Technology/BioMediTech, University of Tampere, Tampere, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors: Johanna
authors: J
authors: Schleutker
authors: The Institute of Cancer Research, London, UK.|Royal Marsden National Health Service Foundation Trust, London and Sutton, UK.
authors: Rosalind A
authors: RA
authors: Eeles
authors: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.|Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal.
authors: Manuel R
authors: MR
authors: Teixeira
authors: Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.|George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors: Lisa
authors: L
authors: Cannon-Albright
authors: National Human Genome Research Institute, NIH, Bethesda, MD, USA.
authors: Elaine A
authors: EA
authors: Ostrander
authors: Department of Urology, Vivantes Humboldt Hospital, Berlin, Germany.|Department of Urology, University Hospital Charité, Berlin, Germany.
authors: Steffen
authors: S
authors: Weikert
authors: Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors: Kathleen
authors: K
authors: Herkommer
authors: Institute of Biomedical Technology/BioMediTech, University of Tampere, Tampere, Finland.
authors: Tiina
authors: T
authors: Wahlfors
authors: Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors: Tapio
authors: T
authors: Visakorpi
authors: Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors: Katri A
authors: KA
authors: Leinonen
authors: Department of Urology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.
authors: Teuvo L J
authors: TLJ
authors: Tammela
authors: The Institute of Cancer Research, London, UK.|Department of Biological Science, University of East Anglia, Norwich, UK.
authors: Colin S
authors: CS
authors: Cooper
authors: The Institute of Cancer Research, London, UK.
authors: Zsofia
authors: Z
authors: Kote-Jarai
authors: The Institute of Cancer Research, London, UK.
authors: Sandra
authors: S
authors: Edwards
authors: The Institute of Cancer Research, London, UK.
authors: Chee L
authors: CL
authors: Goh
authors: The Institute of Cancer Research, London, UK.
authors: Frank
authors: F
authors: McCarthy
authors: Royal Marsden National Health Service Foundation Trust, London and Sutton, UK.
authors: Chris
authors: C
authors: Parker
authors: The Institute of Cancer Research, London, UK.
authors: Penny
authors: P
authors: Flohr
authors: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.|Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal.
authors: Paula
authors: P
authors: Paulo
authors: Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal.|Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors: Carmen
authors: C
authors: Jerónimo
authors: Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal.|Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors: Rui
authors: R
authors: Henrique
authors: Department of Urology, University Hospital Charité, Berlin, Germany.
authors: Hans
authors: H
authors: Krause
authors: Department of Urology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Sven
authors: S
authors: Wach
authors: Department of Urology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Verena
authors: V
authors: Lieb
authors: Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.|Institute of Pathology, University Bern, Bern Switzerland.
authors: Tilman T
authors: TT
authors: Rau
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors: Walther
authors: W
authors: Vogel
authors: Department of Urology, Klinik am Eichert, Göppingen, Germany.
authors: Rainer
authors: R
authors: Kuefer
authors: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: Matthias D
authors: MD
authors: Hofer
authors: Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Luebeck and Borstel, Germany.
authors: Sven
authors: S
authors: Perner
authors: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA.
authors: Mark A
authors: MA
authors: Rubin
authors: University of Utah/ARUP Laboratories, Salt Lake City, UT, USA.
authors: Archana M
authors: AM
authors: Agarwal
authors: Centre for Cancer Genetics Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Doug F
authors: DF
authors: Easton
authors: Centre for Cancer Genetics Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Ali Amin
authors: AA
authors: Al Olama
authors: Centre for Cancer Genetics Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Sara
authors: S
authors: Benlloch
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors: Josef
authors: J
authors: Hoegel
authors: Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, Washington, USA.|Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
authors: Janet L
authors: JL
authors: Stanford
authors: Institute of Human Genetics, University of Ulm, Ulm, Germany.|Department of Urology, University of Ulm, Ulm, Germany.
authors: Christiane
authors: C
authors: Maier
mesh_terms: D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*; D000071230:Transcriptional Regulator ERG / Q000235:genetics
chemical_list: C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human