‘Y’ losing a chromosome could be the first step to cancer

A team of researchers at the University of Arizona have found a potential early warning sign of cancer in otherwise normal-looking male tissues: loss of the Y chromosome in cells. Laura Verdina reports…

Past research shows that cancerous cells in men usually lose their Y chromosome, which is a chromosome responsible for sex determination. In humans, most males carry one copy each of the X and Y chromosomes, while females usually have two copies of the X chromosome. It’s suggested that loss of this Y chromosome gives cancer cells the ability to evade the immune system, explaining why we see this feature in many tumours.

While it has been observed in the past that tumour cells lose their Y chromosomes, this new research finds that this is not limited to only cancerous cells. The team found increased levels of Y chromosome loss in healthy-looking cells located next to tumours. Though the cells would appear visually normal to a pathologist, they had already undergone genetic changes which may predispose them to an increased risk of developing cancer in the future. This chromosomal loss takes place across a gradient, with the most loss being found closest to a tumour, creating a ‘pre-neoplastic field effect’.

“A useful way to think about a pre-neoplastic field effect is to imagine a lawn before weeds become visible. Even though the lawn may look normal, the soil underneath has already changed in a way that makes weed growth more likely,” Dr Dan Theodorescu, the paper’s senior author, told The Naked Scientists.

“The degree of Y chromosome loss increased progressively across a spectrum: from normal tissues of cancer-free men, to normal tissues adjacent to cancer, and finally to the cancer itself. This gradual pattern suggests that Y chromosome loss may be an early event that helps create a ‘fertile ground’ for cancer development, long before a visible tumor forms,” he elaborated.

To discover this, researchers analysed bladder tissue that was removed from men during cancer surgery using a technique called ‘fluorescence in situ hybridization’, or FISH. Tissue samples were stained, and specific chromosomes within the cells were tagged with different coloured fluorescent probes. This allowed samples to be scanned and sent through a computer vision software for analysis, where the computer first detected nuclei within cells, and then automatically counted the number of fluorescent signals corresponding to the X and Y chromosomes. The ratio of X to Y chromosomes detected was used as a quantitative score to measure how much Y chromosome loss was present in a tissue sample.

With this method, the team was able to observe how tissues closest to a tumour had much higher rates of Y chromosome loss than tissues taken further from a tumour, and even lower rates were seen in tissues not involved with tumours.

So, could these findings be useful in creating new methods of cancer detection? Could male patients undergo tissue screening for loss of the Y chromosome as a novel diagnosis method?

“It is important to emphasise that our study does not yet show that screening tissues for Y chromosome loss can reliably locate tumors or be used as a clinical cancer screening test. The current work demonstrates an association between Y chromosome loss and the cancerisation process, but additional studies will be needed to determine the sensitivity, specificity, and predictive value of such testing,” Dr Theodorescu clarified.

Nevertheless, Theodorescu remains optimistic about the potential applications that this finding could have in the future: “Y chromosome loss could potentially help identify men at elevated cancer risk, aid in the detection of premalignant tissue changes, or help guide surveillance of tissues already known to be at risk.”

More work still needs to be done in this area, especially to understand the mechanism by which Y chromosome loss contributes to the development of cancer. Many labs worldwide continue to research not only the Y chromosome but also changes in the X chromosome. These results suggest that cancer detection techniques may look quite different in the next few decades.