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

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Molecular and epidemiological differences have been described between <span style="font-style:italic;">TMPRSS2:ERG</span> 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 <span style="font-style:italic;">TMPRSS2:ERG</span> phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with <span style="font-style:italic;">TMPRSS2:ERG</span> 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 <span style="font-style:italic;">TMPRSS2:ERG</span> fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with <span style="font-style:italic;">TMPRSS2:ERG</span> data was established to replicate the top five candidates. Significant differences (<span style="font-style:italic;">P</span> < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in <span style="font-style:italic;">TMPRSS2:ERG</span> fusion-negative (OR = 0.53, <span style="font-style:italic;">P</span> = 0.0007) and <span style="font-style:italic;">TMPRSS2:ERG</span> fusion-positive PrCa (OR = 1.30, <span style="font-style:italic;">P</span> = 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 <span style="font-style:italic;">SOX9</span> in <span style="font-style:italic;">TMPRSS2:ERG</span> fusion-positive PrCa, which was not evident in <span style="font-style:italic;">TMPRSS2:ERG</span> negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with <span style="font-style:italic;">TMPRSS2:ERG</span> fusion status. <span style="font-style:italic;">TMPRSS2:ERG</span> phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.</span>

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