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Regulatory Features of Fusion-Containing Prostate Tumors Hint at Potential Treatment Strategy

NEW YORK (GenomeWeb) – Canadian researchers have unraveled regulatory features of prostate cancer cases involving structural rearrangements that fuse portions of the TMPRSS2 gene to the gene coding for the ERG transcription factor — an analysis that points to possible treatment strategies for these TMPRSS2-ERG2, or T2E, prostate tumors.

The team brought together whole-genome sequences, chromatin immunoprecipitation sequence profiles, array-based gene expression data, and more for 19 prostate tumors, searching for genomic and regulatory differences between the T2E and non-T2E fusion forms of the disease. Results of these analyses, described online today in Nature Genetics, suggest that the TMPRSS2-ERG2 fusion leads to alterations that include enhanced dependence on the NOTCH signaling pathway.

"Our findings specifically show that fusion-positive prostate cancer is dependent on the NOTCH signaling pathway, which can be blocked chemically in pre-clinical models," corresponding author Mathieu Lupien, a researcher affiliated with the Princess Margaret Cancer Centre, the University of Toronto, and the Ontario Institute for Cancer Research, said in a statement.

Lupien noted that the finding might open up personalized cancer treatment options for as many as half of prostate cancer patients, since cells containing the TMPRSS2-ERG fusion appear targetable with a NOTCH signaling pathway inhibitor called MK-0752 in the researchers' preliminary cell migration assays.

The team reasoned that the T2E fusion would likely have regulatory consequences, since the ERG gene encodes a member of the ETS transcription factor family that gets over-expressed when fused to TMPRSS2, a gene with an androgen-driven promoter.

Using H3K27ac-focused chromatin immunoprecipitation sequencing, for example, the researchers searched for and mapped cis-regulatory elements in 19 fresh frozen prostate cancer samples that came from a collection of tumors already characterized by copy number, somatic mutation, expression, and methylation profiling.

The team then used expression, histone acetylation, and other data to cluster tumors with or without the TMPRSS2-ERG, and began teasing apart distinct so-called clusters of regulatory elements, transcription factor activity, and other regulatory differences between them. It also considered regulatory, expression, and other data for related cell lines.

Results from these and other experiments suggested that T2E-positive tumors tend to be marked by transcriptional patterns reflecting the ERG gene product's ability to alter transcriptional pathways normally governed by the androgen receptor and by FOXA1 or HOXB13 transcription factors, the researchers reported, leading to distinct cis-regulatory element repertoires and expanded clusters of regulatory elements in the fusion-containing tumors.

Among the expression changes prompted by this shift, the team found, was a rise in NOTCH signaling activation that seemed to nudge along the growth and invasiveness of prostate cancer cells with the T2E fusion.

"[W]hile it was previously thought that ERG over-expression was driven by hijacking of androgen-responsive elements within the TMPRSS2 promoter, we show that the molecular processes driving ERG over-expression are more complex," the authors wrote. "To our knowledge, our results are the first to show the expansion of a [cluster of regulatory elements] after a chromosomal rearrangement, with important repercussions on target gene expression."

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