The loss of the Y chromosome in male cells is linked to cancer, and a new finding suggests this change may be an early indicator of the disease. The study revealed that the loss is not confined to within the tumour, but can be found in surrounding tissue that appears healthy, and even in cells that appear completely normal under a microscope.
The study was published in JCI Insight, with the lead author being Dan Theodorescu, director of the University of Arizona’s cancer centre. The majority of cells in the male body typically carry one X and one Y chromosome, but during cell division, the daughter cells may occasionally lose their Y chromosome. As these cells continue to divide, patches of tissue form where some cells possess a Y chromosome while others do not—a phenomenon the researchers describe as mosaic loss of the Y chromosome.
The researchers examined 1,000 archived tissue samples from 11 different organs, collected from 405 men. They used fluorescent in situ hybridisation (FISH) testing, which rendered the X and Y chromosomes visible in more than 4.3 million cell nuclei, and by comparing the signals, they assessed the extent of Y chromosome loss in each sample.
The results showed a clear pattern. Male tissue without cancer retained the strongest signal for the Y chromosome. Tissue of normal appearance immediately adjacent to the tumour showed a weaker signal, while the tumour itself showed the weakest. The level of loss varied depending on the type of cancer, with colorectal tumours showing the greatest loss.
In 49 men, the researchers also analysed the tumour and adjacent, seemingly normal tissue from the same organ. The tumours showed a greater loss of the Y chromosome than their surroundings, whereas tissue from organs distant from the cancer showed little difference compared to men without the disease. The additional loss was thus concentrated in the normal-looking tissue surrounding the tumours.
Although the cells surrounding the tumours appeared completely normal under the microscope, the FISH test revealed that they had already begun to lose the Y chromosome. This does not mean that these cells will necessarily become cancerous, but it indicates a change in the tumour’s environment. In blood cells, loss of the Y chromosome becomes more common with age, but in this study, older age was associated with greater loss in the normal tissue of men with cancer, including in organs distant from the tumour. In men without cancer, no such link was found. The researchers note that aging alone cannot explain why the change was particularly pronounced adjacent to the tumours.
The question remains as to whether the loss of the chromosome contributes to the development of cancer, or whether conditions associated with cancer favour cells that have already lost it. The study cannot provide a definitive answer to the question of causality—it indicates an association, but does not by itself prove a causal link. To demonstrate causality, researchers would need to show that inducing loss of the Y chromosome in cells increases the likelihood of them becoming cancerous, or that preventing this loss reduces the incidence of cancer.
The potential medical application of this finding lies in the analysis of normal-looking tissue adjacent to tumours. If a biopsy misses a small tumour but collects adjacent tissue, the detection of loss of the Y chromosome could alert doctors that further investigation is required. The researchers state that this is a potential future possibility, rather than a current clinical application. The study did not test whether such a biopsy strategy would work in practice; this would require studies following patients over time to determine the accuracy of such a marker in detecting cancer. The key question researchers are now seeking to answer is whether analysis of loss of the Y chromosome can aid in the earlier detection of the disease.
