Title:Recurrent Rearrangements in Prostate Cancer: Causes and Therapeutic Potential
Volume: 14
Issue: 4
Author(s): Nicole M. White, Felix Y. Feng and Christopher A. Maher
Affiliation:
Keywords:
Androgen receptor, gene fusions, genomic instability, prostate cancer
Abstract: DNA damage and genetic rearrangements are hallmarks of cancer. However, gene fusions as driver mutations
in cancer have classically been a distinction in leukemia and other rare instances until recently with the discovery of gene
fusion events occurring in 50 to 75% of prostate cancer patients. The discovery of the TMPRSS2-ERG fusion sparked an
onslaught of discovery and innovation resulting in a delineation of prostate cancer via a molecular signature of gene fusion
events. The increased commonality of high-throughput sequencing data coupled with improved bioinformatics approaches
not only elucidated the molecular underpinnings of prostate cancer progression, but the mechanisms of gene fusion
biogenesis. Interestingly, the androgen receptor (AR), already known to play a significant role in prostate cancer tumorigenesis,
has recently been implicated in the processes resulting in gene fusions by inducing the spatial proximity of
genes involved in rearrangements, promoting the formation of double-strand DNA breaks (DSB), and facilitating the recruitment
of proteins for non-homologous end-joining (NHEJ). Our increased understanding of the mechanisms inducing
genomic instability may lead to improved diagnostic and therapeutic strategies. To date, the majority of prostate cancer
patients can be molecularly stratified based on their gene fusion status thereby increasing the potential for tailoring more
specific and effective therapies.
