A study initiated by a University of Arizona Cancer Center physician-scientist Dr. Dan Theodorescu revealed that the loss of the Y chromosome in men’s body tissue could pave the way for cancer to develop in that tissue. According to research recently published in JCI Insights , the loss of the chromosome, which is common in men as they age, creates a pre-neoplastic field effect, a hidden zone of genetic vulnerability in normal tissue that provides fertile ground for cancer to develop.
Each cell in men’s bodies usually contains one X and one Y chromosome. “Loss of Y” is a common genetic change in men in which an immune cell in the blood loses its Y chromosome. Previous studies showed that the loss of Y in blood cells elevated disease risk, but this study systematically profiled the loss of Y across normal, pre-cancerous and malignant tissues across 11 major human organs.
“We were able to show that the loss of the Y chromosome is found in normal appearing tissues adjacent to a tumor" said Theodorescu, the paper’s senior author and Nancy C. and Craig M. Berge endowed chair for the director of the Cancer Center. “That finding is what makes this discovery so exciting. It suggests we may be looking at one of the earliest signposts of cancer forming.”
The team analyzed 1,000 tissue samples from 405 men, using an automated fluorescent imaging system to inspect more than 4.3 million individual cell nuclei, measuring the ratio of Y to X chromosomes.
In one part of the study, the researchers created detailed maps of bladder tissue that had been removed during cancer surgery. These maps let them see how Y chromosome loss increased as it moved from normal bladder tissue, through early abnormal cells, and into full-blown cancer. The loss of Y in normal-appearing tissue was highest in colon, rectum, esophagus, pancreas and lung cancer.
“We are now thinking of this as a gradient, similar to a hillside that slowly gets steeper," said Theodorescu, who is also a professor at the U of A College of Medicine – Tucson. “The closer the tissue is to a cancer, the more Y chromosome loss we see. That gradient could one day help doctors suspect trouble in biopsies that miss a smaller cancer.”
Theodorescu’s previous related research focused on how the loss of Y in cancer cells gave them the ability to evade the immune system, explaining why the loss of the hormone has been linked to increased mortality from carcinomas.
The study team included first authors Arkadiusz Gertych and Dr. Huihui Ye, along with collaborators from Cedars-Sinai Medical Center, Fred Hutchinson Cancer Center, the University of Washington and the University of California San Francisco.
The study was funded in part by the National Cancer Institute, a division of the National Institutes of Health, under award No. R35CA294022, to Theodorescu.
JCI Insight
Randomized controlled/clinical trial
Human tissue samples
Human Y chromosome pan-organ mapping reveals progressive mosaic loss from normal to cancer
8-Sep-2026
The authors have declared that no conflict of interest exists.