Study of the genetic variations in the TMPRSS2 control regions and their effects on prostate cancer development .

One of the most surprising findings in the prostate cancer field over the last decade was that in 50% of cases, cells have undergone a specific genomic reorganization in which the control region of the TMPRSS2 gene is fused to the protein‐coding part of the oncogenic ets‐related gene (ERG). In this study, we will determine the mechanisms by which the TMPRSS2 control region establishes androgen‐controlled and prostate‐specific gene expression of ERG. We will identify up to the base pair level where the AR and other transcription factors bind to the TMPRSS2 control region. Subsequently, we will develop transgenic models that express the human TMPRSS2‐ERG fusion to study the transcription regulatory process in a prostate environment. Excitingly, we detected Single Nucleotide Polymorphisms (SNP) within the DNA motives upstream of TMPRSS2 to which the AR is binding. Preliminary analyses demonstrate that, at least in vitro, one of these SNPs dramatically lowers the AR transactivation potential. Now, we need to verify the effect of the SNPs on the expression of TMPRSS2 and TMPRSS2‐ERG in prostate cancer. We also propose to search for associations between these SNPs and the frequency of the reorganization and predisposition to (aggressive) prostate cancer.