New Prostate Cancer Gene Mutation Discovered
News May 24, 2012
This week, a team of researchers from the Broad Institute and Weill Cornell Medical College have reported the discovery of mutations in a gene previously unknown to be associated with prostate cancer, a disease that strikes over 241,000 men each year in the United States.
Writing in the May 21 issue of Nature Genetics, the team reports that up to 15 percent of prostate cancer tumor cells analyzed had point mutations in this gene, called SPOP, a rate higher than any other previously discovered prostate cancer gene.
Point mutations involve the switch of one nucleotide molecule on a string of DNA to another.
“There are other genes that are known to be commonly mutated in prostate cancer, including PTEN and TP53,” said Sylvan Baca, co-first author on the paper who works in the laboratory of Broad Institute senior associate member Levi Garraway.
In their analysis, the researchers saw PTEN and TP53 point mutations but these were less frequent than SPOP point mutations. No SPOP mutations were identified in normal tissues from the same patients.
“SPOP is the most frequently mutated gene in localized prostate cancer in terms of point mutations that has been found to date,” said Baca, who adds that other genes are more frequently mutated in prostate cancers that have spread.
In prostate cancer, the genome can be mutated in other ways, including deleting or adding portions of the DNA code or rearranging sections. Point mutations are a way of activating unchecked cell growth across cancer types.
Additionally, the research team noticed that SPOP mutations were not found in prostate cancers bearing another common genetic mutation - the TMPRSS2-ERG gene fusion, which occurs in half of prostate cancer cases.
A gene fusion occurs when two genes located in different parts of the genome become attached together.
“This finding may mean we have discovered a new molecular subtype of prostate cancers,” said Baca. “The fact that the SPOP and TMPRSS2-Erg mutations are mutually exclusive may indicate they represent two alternative paths toward tumorigenesis.”
To arrive at their conclusions, the researchers examined exomes from 112 prostate cancer tumor samples and matching normal tissue.
Exomes are the 1-2 percent of the genome representing the genetic code for protein production.
Exomes are where one typically expects to find a lot of driving mutations in disease, including cancer. They are also the portions of the genomes scientists know the most about.
By focusing on exomes, the scientists could investigate a large panel of tumors - more than has been done before. “This effort is the first to sequence enough prostate cancer tumors to get a broad picture of all of the mutations affecting protein-coding DNA, including those that happen infrequently,” said Baca. “Having a large sample size was essential to finding them.”
Thanks to the recent precipitous drop in the cost of genome sequencing, researchers worldwide can now sequence far more samples than was economically feasible just a few years ago.
SPOP mutations have been seen in prostatic intraepithelial neoplasia (PIN), a premalignant prostate condition. This fact suggests SPOP mutations might arise early on and could be one of the founding events of a prostate tumor.
Findings from the Nature Genetics paper represent the second installment of a joint prostate cancer gene discovery project from the laboratories of Garraway and Mark Rubin, professor of pathology and laboratory medicine at Weill Cornell Medical College.
In February 2011, the group reported in Nature on a set of seven full prostate cancer genomes - those included the exomes plus the other 98-99 percent of the genome that does not code for proteins.
The group is now working on a larger set of whole genomes to reveal other prostate cancer gene anomalies.
“These findings may open up new avenues into cellular processes relevant to prostate cancer that we did not previously appreciate,” said senior author Garraway, who is also an assistant professor at Dana-Farber Cancer Institute and Harvard Medical School. “Now, we must turn increasing attention to the specific biological roles of these newly identified cancer genes and what types of new therapeutic avenues they might reveal.”