Scientists from the Dana-Farber Cancer Institute have found some male cancer cells, those with X and Y chromosomes, show signs of having their X chromosome silenced.
In normal mammal 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 with most male cells, neither the X nor the Y needs to be inactivated.
In some cancer cells, however, this rule of thumb is broken.
The study used publicly available DNA samples from cancer patients around the world. Analyzing thousands of genomes representing more than 30 different cancers, researchers found the gene responsible for silencing the X chromosome – known as X-inactive specific transcript, or XIST – is highly expressed in a wider variety of cancerous tissues than they'd ever suspected.
The gene is a non-coding sequence made of RNA found in the cells of placental mammals that plays a key role in the silencing of genes on X chromosomes.
In genetic males, the silencing of the X chromosome is rare but not unknown. It can occur in conditions where the chromosome is duplicated, such as in Klinefelter syndrome (where two or more X chromosomes accompany a Y chromosome). It can also occur in a scattering of cells early in development and, sometimes, testicular germ cell tumors.
Such sex cell cancers were strongly represented among the 4 percent 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.
"We were very surprised by this result since XIST is a transcript typically used to classify female cancers, and so we wanted to ensure that this was not merely a result of misannotation," says cancer geneticist and oncologist Srinivas Viswanathan from the Dana-Farber Cancer Institute in Boston.
"Yet, we do, in fact, see that some male cancers of diverse subtypes activate XIST and display features of X inactivation."
Researchers aren't sure why that is, but they have a few ideas. Cancers proliferate rapidly, and this can lead to mistakes, like multiple copies of the same chromosome. For instance, the authors sometimes found two X chromosomes in male cancer cells.
Perhaps when this occurs, X inactivation is triggered to maintain genetic stability, allowing a cancerous tumor to better survive and thrive.
"Another possibility 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," says Viswanathan.
It's not often that scientists consider how genetic differences between the sexes might impact cancer therapy and recovery, but the new findings suggest there is a distinction in how cancer cells invade the body and cause destruction.
The study was published in Cell Systems.