New Research on FL Subtypes

Some very cool and potentially important research in Blood Cancer Journal this month. It's called "Identification of Genetic Subtypes in Follicular Lymphoma." It's a straightforward title for some research that is fairly complicated, though its implications are easier to understand. There is a lot of genetics in here, and I found myself getting lost at times, but as I said, its implications are easier to understand. I'll do my best to give you the important stuff.

Some background, first. Cancer researched changed for the better about 20 years ago, when the Human Genome Project finished mapping al of the genes in the human body. That mattered because it allowed researchers to start looking more easily at the genetic basis for cancer. That is, once they saw where genes were supposed to be, they could more easily see that they had moved or changed, and they could figure out that some changes caused health issues like certain cancers. 

Over time, that has made it easier for researchers to identify specific genetic bases for certain cancers. Knowing the genetic basis for something allows other researchers to create targeted treatments. I don't go into much detail when I talk about these things here, because it's usually not necessary. I'll say something like "This treatment helps stop the cancer cell from growing because it shuts off a switch that tells a gene to create an enzyme that enables a protein to tell the cancer cell to keep growing." But that, in a very oversimplified way, is how genetics works in cancer treatments. It's about figuring out which gene is giving instructions that cause a long chain that lets cancer cells grow an survive.

So one of the many types of cancer research is trying to classify certain cancers based on their genetics. As I said, lots of cancers have had this happen (including DLBCL). But so far, that hasn't happened for Follicular Lymphoma. Until now, possibly.

The researchers who wrote this article looked at DNA samples of 713 FL patients before they had treatment. Then they did some DNA analysis and found that there were 5 different genetic subtypes for FL -- 5 different ways that certain genes were expressed. This is important. FL is often thought about as a single disease. But at the same time, if you talk to any other FL patient, you see just how heterogenous the disease is -- how different it shows up. Some us (like me) can watch and wait for a couple of years. Others need treatment immediately. But we both might be stage 3 grade 1/2. And those two people will respond to the same treatment in very different ways.

I don't want to confuse things too much with a lot of detail (which will confuse me, too). But these are the 5 subtypes that the researchers identified:

CS, with affected genes CREBBP and STAT6

TT, with affected genes TNFAIP3 and TP53

GM, with affected genes GNA13 and MEF2B

Q, which stands for quiescent, which means "motionless" or "resting." This genetic subtypes often included patients with stage 1 disease and showed fewer mutations than the other types.

AR, with mutations of the mTOR pathway. This genetic subtype was the one most often associated with advanced-stage disease.

If you google those specifc genes (like CREBBP), you can find more information about what they do. But they generally boil down to the general description I wrote above -- they tell a protein to allow something to happen that leads to a chain of events that keeps a cell alive and growing longer than it should be.

The researchers looked at a second database of FL patients who had received treatment to verify all of this, and to figure out the outcomes for these subtypes. 

That's where it gets really interesting. They can speculate what the implications might be for these genetic subtypes. For example, they think mTOR inhibitors might be an effective treatment for the AR subtype. The CS and GM subtypes might respond to epigenetic modulation (like Tazemetostat). TT might do well with chemotherapy-free treatments. Their hope is that future research will help sort all of that out. But this is a good start.

One other interesting bit from the research -- they were able to look at a group of patients with transformed FL (slow-growing disease that turns into a different, fast-growing disease like DLBCL). They found that early transformation (soon after diagnosis) had stable genetics, while late transformation had unstable genetics. In other words, the subtype that might have shown up on a genetic test soon after diagnosis wouldn't be the same as one that shows up years later at transformation. This is just my speculation, but that would seem to be why it's so hard to find a biomarker to identify transformation (or even POD24) before it happens. The tests miss it because it isn't there yet. They do recommend genetic testing often to pick up on these changes.

All of this is very early research, and most of the practical stuff (like which subtypes will result in certain treatments being more successful) is just guessing. And even if further research confirms the subtypes, it's still not that simple -- there are lots of other factors that go into why a treatment does or doesn't work (otherwise, everyone with a EZH2 positive FL would respond to Tazemetostat, which isn't the case). 

But it's a start, and possibly a good start, in figuring out why we can all have such different forms of the same disease when so many things look the same.