Why Do More Men Get Cancer Than Women? X Chromosome May Hold A Key

(Courtesy of the National Institutes of Health)
(Courtesy of the National Institutes of Health)

More men get cancer than women do, and more boys than girls. With certain cancer types, a lot more. The American Cancer Society says about half of men get cancer at some point, compared to closer to one-third of women. Why?

It's long been a puzzle, but some Boston-based research just out in the journal Nature Genetics finds a possible key in the X chromosome. (Grade school biology reminder: Females have two Xs, males have an X and a Y.)

I spoke with Dr. Andrew Lane of the Dana-Farber Cancer Institute, co-senior author of the paper. Our conversation, lightly edited:

How would you sum up what you found?

We were interested in what is a longstanding observation, that men get cancer more than women, and this is across just about all cancer types. There are very few cancers that are not 'male-biased,' meaning that in a given cancer type — say, colon cancer — more men than women get that per year. And some of them are very biased, like two or three times higher in males.

It’s been blamed on environmental exposures for a long time — men smoke cigarettes more than women, and men work in factories more, so they’re exposed to more dangerous chemicals. But that was probably not the entire story. For example, pediatric leukemias and brain tumors, the common cancers that happen in kids, are also male-biased to some extent.

So this was the mystery...

Exactly. So we used cancer genetics to ask about differences between male and female cancers. We dug into sequencing data that had been generated over the last 10 years as part of The Cancer Genome Atlas, a project funded by the National Institutes of Health and the National Cancer Institute. And we simply asked if there are genes that are more likely to be mutated in male vs. female cancers.

We were specifically interested in tumor suppressor genes. These are genes that normally are in all of our cells, and they protect the cells, if you will, from cancer. In cancers, those tumor suppressor genes are often mutated or deleted in a way that they’re no longer functional.

When we looked across the whole genome, in which there are about 20,000 genes, the only genes that were mutated more frequently in male cancers than female cancers were on the X chromosome. So of all these genes, everything we found that had a male bias was on the X chromosome. And that was already interesting.

As you know, males have an X and a Y chromosome, and females have two Xs, and that’s what makes us male and female. What is fascinating is that evolutionarily, one copy of the X chromosome gets shut down in all cells. That’s thought to be to balance out the gene expression, because males only have one X and females have two.

So because of that, you would have assumed that if there’s a tumor suppressor gene on the X chromosome, it would be equally likely to be mutated in a male or a female, because they each essentially have one that’s active. The other one is supposed to be shut down.

So that didn’t make a lot of sense. But it turns out that for somewhat unclear reasons, about 50 or so genes of the 800 on the X chromosome escape this process called 'X inactivation' — they escape X inactivation routinely, in all cells in the body. There’s a complicated biology behind why this is the case. but about those 50 do, so that means female cells actually have two copies of those genes whereas males have only one. And believe it or not, all the genes we found that were mutated more often in male cancers were those genes, those escaped genes.

To put it another way, females are protected from cancer to some relative extent because they have two copies of these genes whereas males only have one. So if they’re going to get a cancer that those genes are involved in, they have to mutate them twice, whereas males only have to have one mutation.

We could back-calculate what percentage of the male bias in a particular cancer type was related to these genes, and it was variable but in some it was up to 80 percent of the excess male cases were related to mutations in these particular genes.

So that could explain most of the cancer gap?

I think it’s a significant proportion, but it’s not most and it’s not all. There are lots of things that are differences between males and females that we’ve recognized for a long time, like hormones: the difference in the levels of estrogen and testosterone. They probably have something to do with it. There are probably multiple other factors.

One implication is that if you have a given cancer type in two patients sitting in front of you in the clinic, a male and a female, they’re actually different not just in the fact that they’re a male and a female, but in that the genetics that are driving their cancer might be different.

How might this affect treatment eventually?

The first step is that it means that we need to make sure we are including enough males and enough females in cancer research — clinical trials or other lab-based studies — to understand the differences. It’s relevant even down to experiments in animals in the laboratory.

We also did some research about how many cancer cases you would need to identify these genetic differences fully. We basically said we’re only scratching the surface, because in some of the cancers that we studied we just didn’t have enough cases in total to tease out these differences between male and female cells. So it means that we need to study a lot more cancer cases just to even figure out the differences in the first place.

And treatments tailored to male or female patients?

We’re really having an explosion of so-called precision cancer therapy, where we sequence the DNA in a tumor, figure out which particular genes are altered, and there are many therapies in development that target those specific genes.

So if it turns out that males and females are much more likely to have one pathway or another mutated in their cancers, it could mean that some of these precision-type therapies are more likely to benefit a male or a female.

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Carey Goldberg Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.



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