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Molecular Subtype of Prostate Cancer Validated with Funding from PCF

Defect in SPOP gene found in up to 15 percent of all prostate tumors, aggressiveness yet to be determined

May 21, 2012 -- A collaborative research team comprised of scientists from Weill Cornell Medical College, the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute validated a distinct subtype of prostate cancer that accounts for up to 15 percent of all diagnoses, many of which occur in early stages of prostate cancer. Their findings were reported May 20 in the online version of Nature Genetics.

Prostate Cancer Foundation funding supported several of the study’s authors, including co-senior investigators Dr. Mark A. Rubin, The Homer T. Hirst Professor of Oncology in Pathology and vice chair for experimental pathology at Weill Cornell Medical College as well as Dr. Levi Garraway, senior associate member of the Broad Institute of MIT and Harvard.

Under Drs. Rubin’s and Garraway’s leadership, the team identified novel mutations in the SPOP gene, alterations unique to prostate cancer. Normally SPOP genes perform housekeeping functions in the cell, such as determining what to keep and what to throw out. The SPOP mutations occur at places known to be important to this function and may alter how cells tag proteins for disposal. The researchers speculate that accumulation of protein trash or failure to retain proteins that check unrestrained cell growth may be drivers of prostate cancer.

And because the mutations were found in early-stage disease, the researchers are particularly hopeful this might act as a warning sign biomarker. “This could be one of the switches that turns prostate cancer on,” says Dr. Rubin.

The researchers also believe these findings represent a distinct molecular class of prostate cancer disease—apart from the more common ETS gene fusion class that occurs when the TMPRSS2-ERG genes abnormally fuse. The ultimate aim is to tailor therapy to each class of prostate cancer in order to personalize treatment. Taken together, the SPOP mutation and ERG gene fusions, which are mutually exclusive, may account for up to 65 percent of disease.

“While there is still a need for increased discovery, it does appear that the overall genetic landscape of prostate cancer is taking shape. Better understanding of the biology and possible therapeutic avenues linked to these alterations has become a very high priority,” says Dr. Garraway.

While the current study looked only at the portion of the genome that produces proteins-- a sequencing method known as “whole exome” mapping-- earlier work by this same research team vetted the entirety of prostate cancer DNA in seven tumors via whole genome sequencing as a way to discern global changes and patterns of abnormality. As reported in a February 2011 Nature paper, they showed that areas of the genome had been unexpectedly rearranged.

Researchers zeroed in on SPOP for exome sequencing after spotting potential genetic abnormalities in the gene in the broader, less targeted genome-wide studies.

One of the study’s authors says continued research on the SPOP mutation may be one of the breakthroughs needed to better understand prostate cancer tumor biology and that this could potentially benefit the approximately 25,000 men per year in the U.S. who will be diagnosed with tumors containing the SPOP mutation. Moving forward, these researchers will attempt to define the specific biological roles of several new prostate cancer genes, including SPOP, and characterize genomic alterations that emerge through continued discovery. The will also attempt to determine if the SPOP mutation is associated with aggressive disease, which would further enhance the discovery of this mutation in prostate cancer.

Funding for the study was provided by the Prostate Cancer Foundation alongside a grant from the Starr Cancer Consortium, the National Institutes of Health, the Early Detection research Network of the NCI, the Kohlberg Foundation and the United States Department of Defense.

Read more about the Challenge Award reciepients working on the SPOP mutation.

Learn more about the seminal work of Dr. Levi Garraway and Dr. Mark Rubin.

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