Distinct Molecular Subtype of Prostate Cancer Discovered

Examination of 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.

The novel mutations in the gene encoding for the Speckle-type Pox virus and Zinc finger protein (SPOP) in numerous patient tumors, is thus far unique to prostate cancer and so represents a distinct molecular class that might assist in cancer diagnosis and treatment.

A collaborative study under the auspices of the Weill Cornell Medical College (New York, NY, USA) looked at different drivers of cancer, which are mutations in specific genes. It focused on the 1% to 2% of DNA in the genome that codes for proteins, and, as such, is one of the largest whole exome sequencing studies. The team 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. DNA from tumors and normal samples was also analyzed by single nucleotide polymorphism (SNP) 6.0 arrays (Affymetrix; Santa Clara, CA, USA) to detect somatic copy-number alterations. In addition, transcriptome sequencing (ribonucleic acid RNA-seq) was performed on 22 exome-sequenced tumors and 41 independent samples.

The scientists found three genes significantly altered in the prostate cancers, but not in noncancerous tissue. In addition to SPOP mutations, which occurred in 6% to15% of tumors across multiple independent cohorts, they found mutations in the Forkhead box protein A1 (FOXA1) and the mediator of RNA polymerase II transcription, subunit 12 homolog (MED12) genes, each of which are found in about 4% of patient tumors. Further examination revealed the interesting nature of SPOP mutations. SPOP belongs to a class of proteins known as ubiquitin ligases, whose role is to mark other proteins in the cell for degradation. The mutations the team discovered all occur where the SPOP protein binds to the other proteins it should tag.

Levi A. Garraway, MD PhD a senior author and assistant professor at the Dana-Farber Cancer Institute (Boston, MA, USA) said "This prostate cancer subtype appears to contain abnormalities in cellular processes that are quite new to prostate cancer researchers, and should open up many future avenues for enhanced understanding of the disease. Going forward, we will attempt to define the specific biological roles of several new prostate cancer genes, and we will characterize new prostate cancer genomic alterations that are emerging through ongoing discovery efforts." The study was published May 20 2012 in the journal Nature Genetics.

Related Links:
Weill Cornell Medical College
Affymetrix
Dana-Farber Cancer Institute