Study: The Male X Chromosome Is Silenced in Some Cancer Types – Prevention Magazine

Experts explain how some cancer types are inherited through specific genes.
For years scientists have been working on ways to cure cancer. And while, unfortunately, that is still a ways away, researchers are making headway in what we know about types of cancer. A recent study identified a difference between cancer cells and healthy cells—the X chromosome.
Before we delve into the nitty-gritty of the study, you might be wondering what the X chromosome does or what makes it important. In healthy human cells, the X chromosome is only muted when a female cell has a pair of Xs to choose from. Randomly turning off an extra X is the body’s way of balancing the chromosome dosage of both males and females. But if there is just one X chromosome, as is the case with most male cells, neither the X nor the Y needs to be turned off. In some cancer cells, however, this rule is broken.
The groundbreaking study published in Cell Systems used publicly available DNA samples from cancer patients around the world. After analyzing thousands of samples representing more than 30 different cancers, researchers found the gene responsible for silencing the X chromosome (the X-inactive specific transcript, or XIST) is seen often active in a wider variety of cancerous tissues than they’d ever suspected.
“We were very surprised by this result since XIST [the X chromosome in-activating gene] is a transcript typically used to classify female cancers, and so we wanted to ensure that this was not merely a result of misannotation… we do, in fact, see that some male cancers of diverse subtypes activate XIST and display features of X inactivation,” says Srinivas Viswanathan, M.D., from the Dana-Farber Cancer Institute in a press release.

In genetic males, the silencing of the X chromosome is rare but not unknown. It can occur in conditions where the chromosome is duplicated. It can also happen in a scattering of cells early in development and, sometimes, testicular cancer.
Such sex cell cancers were strongly represented among the 4% of male cancers identified with a silenced X chromosome. Yet surprisingly, a quarter of the remainder was associated with non-reproductive cancers, like those of the brain, skin, lung, and thyroid.
At this point, researchers are still unsure why these different kinds of cancer are displaying X chromosome silencing, but they have a few theories.
Cancers are known to spread rapidly, and this can lead to mistakes, like multiple copies of the same chromosome during cell reproduction. For instance, the authors in this study sometimes found two X chromosomes present in individual male cancer cells. This could potentially lead to X silencing being triggered to maintain genetic stability, allowing a cancerous tumor to better survive and thrive.
“Another possibility,” says Dr. Viswanathan, “is there are some important genes on the X chromosome that, when silenced, enable the cancer to grow. We will investigate this in future studies.”
This new research is important because, “The more we learn about why cancer happens, who it may happen to…We can better protect those at risk…Instead of reacting to cancer…We are getting better at preventing cancer,” says Jessica Jones, M.D., oncologist with McGovern Medical School at UT Health Houston and attending physician with Memorial Hermann.
While the findings don’t have any direct clinical impact, the study highlights the need for researchers to take genetic sex into account when searching for new therapeutic targets regarding cancer treatments. Researchers tend to ignore sex when they analyze the gene expression of cancer cells, which is likely why the XIST connection was missed previously.
Given that these new findings were only made possible through new technology, it goes to show that these advancements are “going to be more and more important in cancer care,” says Dr. Jones.
So now that we know that the XIST gene exists in male cells, Dr. Jones says that, “It’s our job to one: Figure out what other cancers might [the gene] be involved in, and also, two: How can we make sure that their potential daughters and grandsons [don’t develop cancer],” given the path of inheritance.
As far as future studies, “We need to continue to do outreach and find all types of people with cancer (white, Black, hispanic, asian, etc.) to look for these genes as our technology improves so we can be better at prevention and early detection,” says Dr. Jones. “Because if we can’t prevent it…we can at least know who to look at, where to look at, and look at it early…” she adds.

Madeleine, Prevention’s assistant editor, has a history with health writing from her experience as an editorial assistant at WebMD, and from her personal research at university. She graduated from the University of Michigan with a degree in biopsychology, cognition, and neuroscience—and she helps strategize for success across Prevention’s social media platforms. 

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