ORLANDO, FL USA (UroToday.com) - Dr. Christopher Barbieri presented his work evaluating the role of SPOP mutations in prostate cancer. SPOP point mutations were identified in prostate cancer by his group after whole exome sequencing in 2012, but the functional significance of these mutations had yet to be explored.
Some prostate cancers were also recently shown to be hallmarked by chromoplexy, a mechanism where multiple genomic alterations occur simultaneously while multiple chromosomal sites are broken, ligated, and rearranged, often associated with loss of some genetic material. Interestingly, SPOP mutations were mutually exclusive from the well-known ETS family rearrangements, leading Dr. Barbieri to evaluate the association of chromoplexy, SPOP mutations, and DNA repair pathways.
Using an elegant cell-line model, he was able to show that under normal conditions, DNA damage is repaired via homologous recombination (HR), which is a high-fidelity repair pathway. However, when the level of SPOP is reduced, cells are forced to repair DNA damage using nonhomologous end joining (NHEJ), which is error-prone. This model would potentially explain the phenomenon of chromoplexy and has therapeutic ramifications because cells which are dependent on NHEJ repair tend to be sensitive to both platinum adducts and PARP inhibitors.
He closed by noting that platinum-based chemotherapy has been used in prostate cancer before but did not show benefit. He reasoned that a signal may have been lost because only 10-15% of patients harbor SPOP mutations. Appropriate patient selection which matches tumor biology with rationale-based therapy may therefore result in better oncologic outcomes.
AUA/NCI Specialized Programs of Research Excellence (SPORE) Joint Workshop
Presented by Christopher E. Barbieri, MD at the American Urological Association (AUA) Annual Meeting - May 16 - 21, 2014 - Orlando, Florida USA
New York, NY USA
Written by Phillip Abbosh, MD, PhD, medical writer for UroToday.com