SAN FRANCISCO, CA USA (UroToday.com) - The keynote lecture this year was given by Dr. Levi Garraway. He provided a thought-provoking discussion of the way prostate cancer genomic evolution differs from genomic evolution of other malignancies, and how certain gene mutations may actually drive the evolution of the cancer genome.
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He began by describing how his lab identified mutations in SPOP, a ubiquitin-ligase enzyme, by using next-generation sequencing. The mutations were identified in the substrate binding cleft, leading him to hypothesize that SPOP mutation allows the buildup of oncogenic substrates because the protein is not able to target substrates for degradation by the proteasome. No definite SPOP targets have been identified yet.
Dr. Garraway also described mutations in CHD1, the protein product of which compacts chromatin. He reported the exciting discovery that prostate cancers with this mutation had a markedly higher number of genomic rearrangements. He related the process of genomic evolution to the evolution of novel species, which occurs via a gradual pathway or a pathway where periods of stability are interspersed with periods of accelerated evolution (punctuated equilibrium). He drew on the recently described process of chromothrypsis (‘chromosome catastrophe’), in which dozens to hundreds of rearrangements happen simultaneously during mitosis. His lab investigated whether this process takes place in prostate cancer and showed that it actually does not. Instead, prostate cancer rearrangements occur through a novel pathway, which they refer to as chromoplexy. During chromoplexy, multiple genomic sites are geographically juxtaposed, possibly around transcription hubs. At that time, chromosome breaks lead to loss of genomic sequence, then “closed” or “chained” rearrangements. These chained rearrangements can be detected in 88% of prostate cancers and are subclonal. Additionally, chained rearrangements disrupt both oncogenes and tumor suppressors. He also demonstrated that chromoplexy happens in other malignancies too, but that the prostate cancer genome seems to more frequently evolve via this pathway.
He closed by returning to his metaphor with the evolution of species, suggesting that prostate cancer genomic evolution seems to be more like punctuated equilibrium, and stated that if the cause of chained rearrangements could be identified, novel strategies at prevention of prostate cancer could be developed.
Highlights of a presentation by Levi Garraway, MD, PhD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Dana-Farber Cancer Institute, Boston, MA USA