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A Trade-off Between Skin Protection and Testicular Cancer Risk


This is SCIENCE FRIDAY. I'm John Dankosky. Ira Flatow is away. When we think of nature selection, we usually think about the traits we can see; the beaks of the Galapagos finches or camouflage in moths, but it's also happening on a cellular, genetic level, and sometimes this survival of the fittest can bring along its own negative side effects.

In a study published this week in the journal Cell, researchers analyzed thousands of genetic variations to examine their links to increased cancer risk. They stumbled upon one mutation that had an interesting evolutionary connection between skin protection from UV rays and an increase in testicular cancer risk.

Here to discuss the results of this new study is Gareth Bond, one of the authors. He's a molecular biologist and member of the Ludwig Institute for Cancer Research at the University of Oxford. Thank you so much for joining us.

GARETH BOND: Oh, thank you. That was a great introduction. You don't need me.


DANKOSKY: Well, we'll need you for at least a few minutes to explain it and maybe you can tell us about the gene P53 that you're looking at and tell us why it's so important when we're talking about cancer.

BOND: Sure. Well, you know, so unfortunately, Doug Bell couldn't be here today, the other primary lead author on this because up at NIH and is affected by the shutdown. But what we're really both interested in is contributing to a large field of personalization of medicine. And we, as molecular biologists, are very interested in not only finding the genetic markers that associate with cancer risk, but understanding the chemistry or how they elicit their effects, how they affect cancer risk.

And so we focus in on this protein that you're talking about, P53, because it's clear that it's one of the most important genes that we know of in cancer. It's mutated somatically so in the actual cancer cells. And over 50 percent of human cancers, very unfortunate families around the globe who have a single mutation in the P53 gene have an incredible high risk of developing cancer within their lifetime.

So we reason that if we want to understand the biochemistry behind these cancer-associated mutations that are found in a large part of the population, that would be a good bet to, you know, place our bets.

DANKOSKY: So tell us more about how the P53 protein protects against cancer in the body in general.

BOND: Well, I think a good visual is when you go out into the sunshine and you get UV radiation and what happens when UV hits our cells is that it can damage our DNA and that damage of - so that's stress, of course, for a cell. And, of course, if you could just randomly damage your DNA, but you could also affect key genes, that if they get bad mutations, can really turn a cell to a cancer cell.

And so what P53's job normally is to sense that and to make the right decision for the cell. So if the DNA is damaged so bad it actually makes the cell commit suicide so it's cleared from the body. So it's a real good natural defense mechanism against cancer.

DANKOSKY: So a great natural defense mechanism against cancer. So how is this actually connected then to testicular cancer? What did you find?

BOND: Well, that's a really interesting question. So what we did is we - so P53 turns on a lot of genes. So it functions - anyone in the know, it's a transcription factor. It binds some very specific sequences and turns on its genes to elicit this tumor suppressive effect. And so we looked for all the - you know, there's over at least 62,000 of these types of mutations that we look at that we call snips that have been associated or linked with cancer.

And we said, how many of these snips are in that code that P53 recognized? And it turns out - I mean, we could maybe mine a little more deeper, but it's really obvious there's only one and that's in this gene called kit ligand. And interestingly, P53 is also one of the most well-studied genes in the genome and our collaborators, Neil Box and Graeme Walker, went on to show that in the skin, P53 senses the UV damage and then up-regulates this gene that then gets sent out of the cell - the protein product of that gene - and it stimulates those cells in our skin to tan.

And that tanning is actually also a natural defense mechanism to stop, you know, massive sun burning or eventually skin cancer later on, you know, in an individual. But what was interesting was that this snip, or this mutation, was in our screen because it was found to associate with differential testicular cancer risk. And what was quite interesting is that this - the effect that it has on testicular cancer risk is a lot stronger than a lot of the similar mutations in the genome.

DANKOSKY: And it is linked to this idea that testicular cancer is much more common in Caucasians than it is in, say, African-Americans. How much more common is it in Caucasians?

BOND: Well, the estimates that I know of - again, I'm not a real testicular cancer expert, but the estimates that we have in the literature are four to five to six-fold different between Caucasians and Africans. And there's definitely a strong genetic component to testicular cancer.

DANKOSKY: Does this study tell us anything, also, about why testicular cancer is relatively so easy to cure? It has got a pretty good cure rate, comparably speaking.

BOND: It's a very good cure rate. It's at 90 percent. And at least the, again, the numbers that I have access to. And what's interesting is that it can metastatic disease, so that cancer that's already spread to other organs can also be well treated with DNA damaging chemotherapies. And I'm very glad you asked that because we think - or our work would suggest a possible working model to work off of why that could be the case.

And in the sense that kit ligand is not only important in the skin, but it's also important in the testes and the gonads and these types of cells. And so P53 is often just activated there to make sure that the genomes remain stable. And that little bit of activation could stimulate kit ligand in one cell to then be secreted and affect the proliferation of other cells.

Now, this is just a hypothesis now, but one that we're following up and so interestingly, that would mean that the cell, the cancer cell that's dividing, could require P53 or want to keep P53 intact. And, of course, P53 senses that DNA damage that is elicit by chemotherapies. So it's not only giving the cells a growth advantage, but once those cells become cancerous, P53 is there to respond to the chemotherapy and potentially give testicular cancer that good cure rate.

DANKOSKY: You seem pretty excited about the idea of studying genomes to help in cancer treatments. What else can we maybe hope to expect coming down the pike in the next several years?

BOND: Well, there's a big effort between, you know, hundreds of labs throughout the world, both looking at the inherited genomes, so those that were born with them that are in a lot of the cells of our body or almost all, as well as the cancer genome. So cancer as it progresses, it accumulates and selects for a lot of mutations.

And we're already seeing really incredible stuff happening using cancer genomics to develop novel therapies. And so all of us in the cancer genomic fields think that that's very exciting. Now, what's interesting about the inherited genetics - so the stuff that we're born with, is that we hope by collecting these mutations and these very important genes that we're going to be able to start piecing them together and really identify those individuals who are at a very significant increased risk for developing cancer.

And that maybe we can adjust their screening and look very closely at them and catch the cancer at a time where we can remove it easily, for example, surgically, and cure more effectively.

DANKOSKY: Gareth Bond is one of the authors of the study we've been talking about. He's a molecular biologist and member of the Ludwig Institute for Cancer Research at the University of Oxford. Thank you so much for joining us today. I appreciate it.

BOND: Thank you so much. Transcript provided by NPR, Copyright NPR.