London: Researchers have uncovered a distinct molecular subtype of prostate cancer, which appears to afflict 15 percent of patients with the disease.
In their study, the investigators at Weill Cornell Medical College, the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute described how they discovered novel mutations in the SPOP (“S-pop”) gene in numerous patient tumours.
The researchers revealed that 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 that the mutations change the way cells tag proteins for degradation, leading to an accumulation of dangerous molecules, which drive the growth of cancer, perhaps from the beginning.
This finding adds to a string of discovery of other genes linked to prostate cancer over the years by this team of researchers, the totality of which is painting a comprehensive picture of how genetic alterations contribute to prostate cancer.
"These studies constitute a unique, meticulous and intensive look at prostate cancer to see the mechanisms driving this disease," said Mark A. Rubin, The Homer T. Hirst Professor of Oncology in Pathology and vice chair for experimental pathology at Weill Cornell Medical College.
"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," he said.
Mutations in SPOP constitute one major pathway, resulting to almost 15 percent of prostate cancer cases.
"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 Levi Garraway, a senior associate member of the Broad Institute of MIT and Harvard, and assistant professor at the Dana–Farber Cancer Institute and Harvard Medical School.
In February 2011, the collaborative groups published a study in which they used whole genome sequencing to detect global changes and patterns of abnormality in seven prostate tumours and compared them to normal tissue samples.
They found that the areas of the genome had been unexpectedly rearranged something similar to what Rubin and his collaborators at the University of Michigan found in 2005 with the discovery of the common recurrent `TMPRSS2-ERG` gene rearrangement, created by the fusion of two different genes.
This current study looked at various drivers of cancer, which are the mutations in specific genes.
It focused on the 1-2 percent of DNA in the genome that contains codes for proteins, and according to Garrais, is as such, one of the largest "whole exome" sequencing studies published on prostate cancer to date.
Dr. Christopher Barbieri, a fifth year urology resident at Weill Cornell insisted that the motivation to search for genes in this way came about because of the observation that SPOP appeared to be mutated in some cases of prostate cancer.
Broad Institute researchers, led by Garraway and Sylvan Baca, completed an exhaustive `exome` sequencing of 112 prostate tumours and normal tissue pairs.
The findings were then verified in another 400 prostate cancer patient samples from other institutions around the country.
Barbieri, Baca and Michael Lawrence of the Broad Institute are the study``s co-lead investigators.
The teams discovered that three genes were significantly altered in the prostate cancers, but not in non-cancerous tissue.
In addition to SPOP mutations, which occurred in 6 to 15 percent of tumours across multiple independent cohorts, investigators found mutations in the FOXA1 and MED12 genes, each of which are found in about 4 percent of patient tumors.
Further examination revealed the interesting nature of SPOP mutations.
SPOP belongs to a class of proteins named `ubiquitin ligases`, whose role is to mark other proteins in the cell for degradation.
The team discovered that the mutations occur where the SPOP protein binds to the other proteins it should tag.
Because these mutations were also found in premalignant lesions, the researchers suspect SPOP mutations occur early in development of the cancer.
However, they do not yet know if SPOP mutations define a more aggressive type of prostate cancer.
Rubin further revealed that SPOP mutations and TMPRSS2-ERG fusion genes never occur in the same tumour.
They are mutually exclusive, implying that two distinct molecular classes of prostate cancer.
Barbieri claimed that the finding of a SPOP mutation may be one of the breakthroughs oncologists have been seeking.
This study has been published online by the journal Nature Genetics.