Luedeke Manuel, Rinckleb Antje E, FitzGerald Liesel M, Geybels Milan S, Schleutker Johanna, Eeles Rosalind A, Teixeira Manuel R, Cannon-Albright Lisa, Ostrander Elaine A, Weikert Steffen, Herkommer Kathleen, Wahlfors Tiina, Visakorpi Tapio, Leinonen Katri A, Tammela Teuvo L J, Cooper Colin S, Kote-Jarai Zsofia, Edwards Sandra, Goh Chee L, McCarthy Frank, Parker Chris, Flohr Penny, Paulo Paula, Jerónimo Carmen, Henrique Rui, Krause Hans, Wach Sven, Lieb Verena, Rau Tilman T, Vogel Walther, Kuefer Rainer, Hofer Matthias D, Perner Sven, Rubin Mark A, Agarwal Archana M, Easton Doug F, Al Olama Ali Amin, Benlloch Sara, Hoegel Josef, Stanford Janet L, Maier Christiane
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Department of Urology, University of Ulm, Ulm, Germany.
Hum Mol Genet. 2016 Dec 15;25(24):5490-5499. doi: 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.
已报道了TMPRSS2:ERG融合阳性和融合阴性前列腺癌（PrCa）之间的分子和流行病学差异。假设存在两种分子上不同的亚型，我们在总共1221例经TMPRSS2:ERG表型分析的PrCa病例中，研究了先前在全基因组关联研究中确定的27种常见PrCa风险变异与亚型特异性的关联。在对一组552例有TMPRSS2:ERG数据的病例和来自五个中心的7650名未受影响男性的发现集进行的荟萃分析中，我们发现有证据支持以下假设：几种常见风险变异与一种特定亚型相关，而非与一般的PrCa相关。在病例对照比较中分析了风险变异（296例TMPRSS2:ERG融合阳性病例与256例融合阴性病例），并建立了一组独立的669例有TMPRSS2:ERG数据的病例来重复验证前五个候选变异。对于rs16901979（8q24）和rs1859962（17q24），在两种亚型之间观察到显著差异（P < 0.00185），它们分别在TMPRSS2:ERG融合阴性PrCa中富集（OR = 0.53，P = 0.0007）和在TMPRSS2:ERG融合阳性PrCa中富集（OR = 1.30，P = 0.0016）。进行了表达定量性状位点分析，以研究风险变异、融合状态和靶基因mRNA水平之间的机制联系。对于17q24处的rs1859962，在TMPRSS2:ERG融合阳性PrCa中观察到候选靶基因SOX9的基因型依赖性表达，而在TMPRSS2:ERG阴性肿瘤中不明显。本研究为前两种与TMPRSS2:ERG融合状态差异相关的常见PrCa风险变异提供了证据。需要对更大规模的研究进行TMPRSS2:ERG表型分析，以确定在PrCa中具有亚型特异性作用的全面变异集。
