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Hum Mol Genet. 2016 Dec 15;25(24):5490-5499. doi: 10.1093/hmg/ddw349.

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

Author information

1
Institute of Human Genetics, University of Ulm, Ulm, Germany.
2
Department of Urology, University of Ulm, Ulm, Germany.
3
Fred Hutchinson Cancer Research Center, Division of Public Health Science, Seattle, Washington, USA.
4
Cancer, Genetics and Immunology, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
5
Institute of Biomedical Technology/BioMediTech, University of Tampere, Tampere, Finland.
6
Department of Medical Biochemistry and Genetics, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
7
The Institute of Cancer Research, London, UK.
8
Royal Marsden National Health Service Foundation Trust, London and Sutton, UK.
9
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
10
Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal.
11
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
12
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
13
National Human Genome Research Institute, NIH, Bethesda, MD, USA.
14
Department of Urology, Vivantes Humboldt Hospital, Berlin, Germany.
15
Department of Urology, University Hospital Charité, Berlin, Germany.
16
Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
17
Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
18
Department of Urology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.
19
Department of Biological Science, University of East Anglia, Norwich, UK.
20
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.
21
Department of Urology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
22
Institute of Pathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
23
Institute of Pathology, University Bern, Bern Switzerland.
24
Department of Urology, Klinik am Eichert, Göppingen, Germany.
25
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
26
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.
27
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA.
28
University of Utah/ARUP Laboratories, Salt Lake City, UT, USA.
29
Centre for Cancer Genetics Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
30
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

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.

PMID:
27798103
PMCID:
PMC5418832
DOI:
10.1093/hmg/ddw349
[Indexed for MEDLINE]
Free PMC Article

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