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The Male X Chromosome Is Silenced in Some Cancer Types

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A new study has found that the X chromosome, of which one copy is typically inactivated in XX female cells, can also be inactivated in some male cancers. The study is published in Cell Systems.

X chromosome inactivation – a vital process

The X chromosome is one of two sex chromosomes that determine biological sex in humans. Females typically have two copies of the X chromosome (XX), while males typically have one X chromosome and one Y chromosome (XY).

During the early development of female embryos, one X chromosome produces a non-coding RNA – i.e., an RNA molecule that is not translated into a protein – called XIST. These molecules coat the surface of one of the X chromosomes, inactivating that copy and “silencing” the expression of its genes.

The process of inactivating one X chromosome in female cells, called “dose compensation”, is vital as it balances the expression of X chromosome genes between XX females and XY males, meaning both sexes express genes from a single X chromosome. However, XIST can also be expressed in males who have multiple copies of the X chromosome, as is the case with conditions such as Klinefelter syndrome, in which males are XXY or even XXXY.

Previous studies have shown that some female cancers can lose the ability to “switch off” one X chromosome. This increases the amount of X chromosome genes expressed, possibly helping to drive the growth of some cancers. Furthermore, XIST expression has also been observed in testicular tumors derived from male germ cells – however, it is unknown whether this is associated with the silencing of the X chromosome.

In the current study, the researchers investigated whether X chromosome inactivation can go awry as part of the genetic abnormalities that drive cancer.

X chromosome silencing signatures in male cancers

The researchers reanalyzed a large amount of publicly available cancer data in a sex-specific fashion. Data was taken from sources such as The Cancer Genome Atlas (TCGA), a database of molecular information – including genetic data – from over 20,000 cancers, covering 33 different cancer types.

Using this genetic data, the researchers identified that 4.2% of cancers labeled as male showed high XIST expression – even similar to levels found in normal female cells. Four samples were detected that were likely mislabeled as male, and three samples were from people with Klinefelter syndrome – these were all excluded from further analysis.

When the researchers investigated the expression of other X chromosome genes and epigenetic changes to the chromosome, they discovered that a subset of XIST-positive male cancers did indeed show hallmarks of X chromosome silencing.

Dr. Srinivas R. Viswanathan, senior author and assistant professor of medicine at Harvard Medical School, explained in an interview with Technology Networks that there were some rather unexpected additional findings. “We found that a significant proportion of testicular cancers (germ cell tumors) express XIST. This is consistent with what has been reported previously and may reflect the expression of XIST within the germ cell of origin for these cancers,” he described. “However, surprisingly, we also found XIST expression in a small percentage of male cancers across diverse other lineages.”

Around 74% of the XIST-positive cases identified were reproductive cancers. However, the remaining 26% were from a variety of other tissues including liver, brain, skin, heart and lung cancers.

Viswanathan expands on these findings, explaining that many of these cancers had a higher-than-normal number of X chromosomes, and hypothesizing that XIST is activated to compensate for the increased dose of X-linked genes. Many cancers have an abnormal number of chromosomes, known as aneuploidy, but it may be the case that is necessary to activate XIST in cancers with multiple X chromosomes.

“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,” Viswanathan added.

Investigation of several other datasets also revealed increased XIST expression in other male cancers at a similar rate, in addition to decreased XIST expression in some female cancers. Overall, this suggests dysregulation of X chromosome activation in both males and females is a relatively rare, but recurring feature of cancer.

Implications for cancer progression and therapy

Activation of processes associated with X chromosome silencing in somatic male cells could present an interesting therapeutic target in the future, but the authors note that more work is required to understand the implications of XIST activation on the initiation and/or progression of cancer.

“In the future, we hope that we will be able to prospectively study this phenomenon in additional tumors via bulk and single-cell profiling, and to mechanistically understand the causes and consequences of somatic XIST activation in male cancers in experimental models,” Viswanathan concludes.

Reference: Sadagopan A, Nasim IT, Li J, Achom M, Zhang CZ, Viswanathan SR. Somatic XIST activation and features of X chromosome inactivation in male human cancers. Cell Syst. 2022. doi: 10.1016/j.cels.2022.10.002

Srinivas R. Viswanathan was speaking to Sarah Whelan, Science Writer for Technology Networks.