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Some male-derived cancers inactive the X chromosome

Another layer of complexity has been added to the process of oncogenesis – a normally female-specific developmental process, called X chromosome inactivation (XCI), can be seen in some non-reproductive male-derived cancers. A recent study, published in Cell Systems, identified higher levels of XIST expression in some male cancers,which leads to XCI.

X (chromosome) marks the spot

The biological sex of females is typically defined by two copies of the X chromosome (XX), whereas the biological sex of males is typically defined by one X chromosome and one Y chromosome (XY). In somatic cells (normal cells of the body and not germ cells), there should only be one functional copy of the X chromosome to balance the expression of X chromosome genes. As a result, female cells ‘turn off’ one of the X chromosomes through a process called X chromosome inactivation (XCI).

During early embryonic development, a non-coding RNA molecule called XIST, is expressed and coats one of the X chromosomes. This leads to silencing and inactivation. The phenomenon is usually female-specific as XIST is only expressed in XX cells.

Researchers at the Dana-Farber Cancer Institute investigated whether XCI was dysregulated in cancer. They found that 4.2% of male-derived cancers had a high expression of XIST. Most of the samples were from reproductive cancers where XCI has previously been described. However, around 25% of the samples were from various other cancers including liver, brain, heart, thyroid and lung.  

Assistant Professor Srinivas Viswanathan, senior author of the paper, said, “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 mis-annotation. Yet, we do in fact see that some male cancers of diverse subtypes activate XIST and display features of X inactivation.”

I wonder ‘Y’ there’s no ‘X’

The researchers analysed publicly available datasets containing genetic and molecular information from thousands of DNA samples from various types of cancer.

They found that some male-derived cancers had XIST expression levels that were similar to normal levels seen in female cells. There were also changes to DNA packaging that suggested an epigenetic mechanism for increased XIST expression in the male cancers.

XIST-expressing male cancers showed features of XCI. By conducting transcriptional output analysis, the researchers showed that there was reduced expression of X chromosome genes. They also found that cancers with a higher number of X chromosomes had higher XIST levels.

Future work

It is important to understand why some male cancers increase XIST to initiate XCI. The study discussed the survival advantages of XCI. Too much genetic instability is damaging for cancer cells, and this can happen when they express several copies of a chromosome, such as the X chromosome. Therefore, by increasing expression of XIST, cancer cells have a mechanism to ‘turn off’ extra copies and avoid an unfavourable genetic event.

Another reason could be to inactive tumour suppressor genes that may be encoded on the X chromosome. More research is needed to understand the implications of XIST activation on oncogenesis, according to the researchers.

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