Researchers discover distinct molecular subtype of prostate Ca

A collaborative research effort into the genetics of prostate cancer has uncovered a distinct subtype of the disease, one that appears to account for up to 15% of all cases.

In the study, researchers from Weill Cornell Medical College, New York; the Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA; and the Dana-Farber Cancer Institute, Boston, describe discovering novel mutations in the SPOP gene in numerous patient tumors, saying this alteration is thus far unique to prostate cancer and so represents a distinct molecular class that might assist in cancer diagnosis and treatment. They suspect the mutations alter the way cells tag proteins for degradation, leading to an accumulation of dangerous molecules that drive the growth of cancer, perhaps from the beginning.

Findings were published online in Nature Genetics (May 20, 2012).

"This study, and our prior findings, tells us that prostate cancer is not just one disease. So far, we have found two main pathways for prostate cancer to develop and this opens the door to development of specialized diagnostic tools and treatments," said co-senior author Mark A. Rubin, MD, of Weill Cornell Medical College.

Mutations in SPOP constitute one major pathway, accounting for up to 15% of prostate cancer cases. The other pathway is the 50% of prostate cancers containing the so-called ETS fusion genes, such as TMPRSS2-ERG.

"While there is still a need for increased discovery, it does appear that the overall genetic landscape of prostate cancer is taking shape, and better understanding of the biology and possible therapeutic avenues linked to these alterations has become a very high priority," said co-senior author Levi Garraway, MD, PhD, of the Broad Institute of MIT and Harvard, and the Dana–Farber Cancer Institute and Harvard Medical School.

Broad Institute researchers, led by Dr. Garraway and Sylvan Baca, completed an intensive exome sequencing of 112 prostate tumors and normal tissue pairs. The findings were verified in another 400 prostate cancer patient samples from other institutions around the country.

The authors found three genes significantly altered in the prostate cancers, but not in non-cancerous tissue. In addition to SPOP mutations, which occurred in 6% to 15% of tumors across multiple independent cohorts, they found mutations in the FOXA1 and MED12 genes, each of which are found in about 4% of patient tumors.

Also, the mutations the authors discovered all occur where the SPOP protein binds to the other proteins it should tag.

"That suggests that there might be an accumulation of proteins in the cell that aren’t cleaned out and this might lead to cancer growth, or the mutations could be removing proteins that help prevent unchecked cell growth," Dr. Rubin said. "We are working hard to understand what is happening."

Because they were also found in premalignant lesions, the authors suspect SPOP mutations occur early in development of the cancer.

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