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

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Luedeke, M and Rinckleb, AE and FitzGerald, LM and Geybels, MS and Schleutker, J and Eeles, RA and Teixeira, MR and Cannon-Albright, L and Ostrander, EA and Weikert, S and Herkommer, K and Wahlfors, T and Visakorpi, T and Leinonen, KA and Tammela, TLJ and Cooper, CS and Kote-Jarai, Z and Edwards, S and Goh, CL and McCarthy, F and Parker, C and Flohr, P and Paulo, P and Jeronimo, C and Henrique, R and Krause, H and Wach, S and Lieb, V and Rau, TT and Vogel, W and Kuefer, R and Hofer, MD and Perner, S and Rubin, MA and Agarwal, AM and Easton, DF and Al Olama, AA and Benlloch, S and Hoegel, J and Stanford, JL and Maier, C and The PRACTICAL consortium, Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status, Human Molecular Genetics, 25, (24) pp. 5490-5499. ISSN 0964-6906 (2016) [Refereed Article]


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Copyright The Author 2016. Published by Oxford University Press. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: 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 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 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.

Item Details

Item Type:Refereed Article
Keywords:prostate cancer TMPRSS2:ERG 8q24 tumour
Research Division:Medical and Health Sciences
Research Group:Oncology and Carcinogenesis
Research Field:Cancer Genetics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:FitzGerald, LM (Dr Liesel Fitzgerald)
ID Code:112381
Year Published:2016
Web of Science® Times Cited:2
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-11-07
Last Modified:2017-11-06
Downloads:5 View Download Statistics

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