The X chromosome is silent in some male cancers

Cancer cells acquire genetic abnormalities that allow them to grow and proliferate
unchecked.
Researchers have now discovered another difference between cancer cells and normal cells: The X chromosome, which is normally only inactivated in XX female cells, can be inactivated
in cancers of different male origin.
The study was published Nov.
9 in Cell Systems
.

"To balance gene expression between sexes, one copy of a female's X chromosome is randomly inactivated
in the human body during normal development.
We wanted to know if this normal developmental process could go wrong in genetically unstable male or female cancer cells," said senior author Srinivas Viswanathan
, a cancer geneticist and medical oncologist at Dana-Farber Cancer Institute.

Using publicly available datasets, including thousands of DNA samples from cancer patients around the world, the team stumbled upon the highly expressed XIST, the gene responsible for turning off gene expression on the X chromosome — about 4 percent
of the male cancer samples analyzed.

While XIST may be expressed in early development of all sexes, X inactivation is thought to be a process
specific to females later in development.
Previous studies have shown that some female cancer cells may lose the ability to shut down an X chromosome, leading to increased expression of X-linked genes, but this ability to inactivate X is still mainly studied
only in female cells.

Of the 4 percent of abnormal male cancer samples, 74 percent came from cancers of the reproductive organs that have been shown to inactivate the X chromosome, but the remaining 26 percent came from samples
from other cancer types.
These cancers include liver, brain, skin, heart, lung, and thyroid cancers
.

"We were very surprised by this result, XIST is a transcript commonly used to classify women's cancers, so we wanted to make sure that this was not just the result of
annotation errors.
" However, we did see some different subtypes of male cancers activating XIST and showing features of X inactivation," Viswanathan said
.

"We have to be aware of the considerations
for using this type of dataset.
These samples are already in the hands of a lot of people, so there's more room for human error," said
Cheng-Zhong Zhang, a cancer biologist at Dana-Farber Cancer Institute.
"This is our biggest source of uncertainty; We have to look creatively at data and find ways
to control it.
”

One possible explanation for this phenomenon is genetic instability
.
Cancer usually has multiple copies of chromosomes, and if a cell happens to have two X chromosomes, it is necessary to inactivate XIST by activating one of them, regardless of whether the cell is in a woman or a male
.

"Another possibility is that there are some important genes on the X chromosome, and when they are suppressed, cancer grows
.
We will investigate this in future studies," Viswanathan said
.

"In a way, gender is the ultimate biomarker because it subdivides the human population, but we don't usually consider how genetic differences between the sexes affect cancer prognosis or treatment response
," Viswanathan said.

Somatic XIST activation and features of X chromosome inactivation in male human cancers