Y Chromosome Loss May Reveal Cancer Beyond Tumours

Cancer may leave a detectable mark beyond tissue that visibly appears cancerous.

Y chromosome loss in normal-looking tissue near cancer

New research indicates that, in men, this mark may take the form of a missing Y chromosome in cells that otherwise appear entirely normal.

That finding emerged from a study comparing tissue from men with cancer with tissue from men without it.

Cells directly adjacent to tumours had greater Y chromosome loss than normal tissue from cancer-free men, while the tumours themselves displayed still more loss.

"What surprised us most was that Y chromosome loss was not confined to the cancer itself," Dan Theodorescu, director of the University of Arizona Cancer Center and senior author of the study, told ScienceAlert.

Most cells in a man's body contain one X chromosome and one Y chromosome. However, when a cell divides, one of its descendant cells can occasionally lose the Y chromosome.

As these cells reproduce, they can create areas of tissue where some cells retain the chromosome and others lack it. Scientists refer to this as mosaic loss of Y.

To establish where these pockets might be found, Theodorescu and his team analysed 1,000 archived tissue samples from 405 males, spanning 11 major organs.

Using fluorescence in situ hybridisation (FISH), they made the X and Y chromosomes visible in more than 4.3 million cell nuclei. By comparing the two signals, the team estimated the level of Y chromosome loss within every sample.

The researchers converted this signal ratio into a score for each sample. This score represents the tissue sample as a whole, which can include epithelial, immune and stromal cells.

A low score does not indicate that every cell in that sample has lost its Y chromosome. The method was checked against measurements of Y-linked gene activity in 25 metastatic prostate cancer samples.

A gradient from healthy tissue to tumours

The findings revealed a gradient. Normal tissue from men without cancer showed the strongest Y signal, whereas normal-looking tissue immediately next to a tumour showed a weaker signal.

The tumour itself produced the weakest signal. Levels of loss differed across cancer types, and colorectal tumours showed the greatest loss.

The researchers had samples of both tumour tissue and neighbouring normal-looking tissue from the same organ for 49 men: 33 with bladder cancer, eight with prostate cancer and eight with other cancers. Among these men, Y chromosome loss was greater in tumours than in the surrounding tissue.

Overall, tissue taken from organs distant from a man's cancer did not differ significantly from normal tissue from men without cancer. The additional loss was concentrated in apparently normal tissue beside tumours. This does not mean that the normal-looking cells will inevitably become cancerous.

"Many of the cells surrounding tumors looked completely normal under the microscope. Yet by the FISH test, they had already begun to show evidence of Y chromosome loss," Theodorescu said.

A reanalysis of existing bladder data found that activity in Y-linked genes generally fell as tissue progressed from precancerous changes towards invasive cancer. In another set of bladder samples, the difference between precancerous lesions and invasive tumours in five individuals narrowly missed the conventional threshold for statistical significance.

These samples were different tissues examined at a single time point, rather than the same cells being monitored as cancer developed.

Age, cause and possible cancer detection

In blood cells, Y chromosome loss becomes increasingly common with age. In this study, older age was linked with greater loss in normal tissue from men with cancer, including organs distant from tumours. This association was not seen in tissue from cancer-free men or in tumours.

According to Theodorescu, ageing alone does not easily account for why the change was particularly apparent beside tumours.

It remains unclear whether loss of the chromosome helps to initiate cancer, or whether cancer-related conditions favour cells that have already lost it. The study cannot separate these explanations.

"Our study suggests an association between Y chromosome loss and cancer development, but it does not by itself prove cause and effect," Theodorescu said.

He said that researchers would need to demonstrate either that deliberately triggering Y chromosome loss makes cells more likely to become cancerous, or that stopping the loss reduces cancer formation. Such experiments could address causation in a way that tissue comparisons cannot.

The possible medical value concerns normal-looking tissue surrounding tumours. If a biopsy fails to capture a small tumour but takes neighbouring tissue instead, Y chromosome loss could one day prompt doctors to investigate further.

"Potentially, yes, although that remains a future possibility rather than a current clinical application," Theodorescu said. The study did not assess whether this biopsy approach is effective.

This would need studies that follow patients over time. They would also have to determine how accurately the marker identifies cancer.

The present research relied on small archived samples, with only 1,000 of 2,917 collected samples passing image-quality checks. Normal tissue from an organ distant from cancer was available from just 10 men.

Whether Y chromosome loss could ultimately help to detect cancers earlier is now a question researchers can investigate.

The research was published in JCI Insight.

This article was fact-checked by Peter Dockrill and edited by Peter Dockrill. Although we take pride in our process, we are only human. If you notice an error, please let us know.