There’s usually more than one right way to get where you want to go. Unless of course, you’re using Apple Maps, then all routes are questionable, but at least have a pretty interface. It turns out there are at least two ways to wind up with prostate cancer, and neither are that attractive—having a gene fusion, or some unknown way without a fusion. Now, in appears that DNA methylation and miRNA 26a might provide an alternative route for prostate cancer progression and could be key to how the “fusion-negative” prostate tumors come about.
The German, U.S., and Italian team explain that a lot of prostate cancers have gene fusions of TMPRSS2 with some member of the ETS family—usually ERG. And in these cases, ERG overexpression seems to be sufficient for cancer. But some prostate tumors don’t have that rearrangement. They’re called fusion-negative, and no one really knows how they become cancerous.
The researchers thought DNA methylation might play a role, so they did a genome-wide MeDIP-Seq and compared methylation patterns among normal, fusion-positive (FUS+), and fusion-negative (FUS-) human tissues. Here’s what they learned:
- They found more than 147,000 cancer-associated differentially methylated regions.
- In a statistical analysis, they saw that FUS-tissues were very different methylation-wise vs. normal and FUS+ tissues.
- EZH2, an H3K27 methyltransferase, was significantly increased in both FUS+ and FUS- tissues.
Here’s where it gets interesting…even though EZH2 was highly expressed in both types, it’s regulated differently in the two tumor samples. In FUS+ tissues, ERG regulated it. But in FUS- specimens, another regulator was at work. The team looked at miRNAs -26a , -101, -138 , -124 , -214 , and let-7b since they’ve previously been suggested to regulate EZH2.
Webinar: Genome-wide increase in differential DNA Methylation in TMPRSS:ERG Fusion Gene Negative Prostate Tumors
Presented by: Dr. Michal-Ruth Schweiger, Max Planck Institute for Molecular Genetics
Tuesday, January 29, 2013 10:00 PST
They all showed expression differences of these miRNAs between normal and cancerous tissues, but only one, miRNA 26a, showed differences in expression between FUS+ and FUS- samples.
“The observed increase in differential methylation events in fusion-negative tumors can explain the tumorigenic process in the absence of genomic rearrangements,” they conclude.
This paper had more twists and turns than a spy novel so check it out yourself at Cancer Discovery, November 2012.