Y Chromosome Loss in Men May Signal Early Cancer Development: What a New Study Found Across 11 Organs

A study headed by Dr. Dan Theodorescu, MD, PhD, Arizona Cancer Center, found that Mosaic loss of Y chromosome (mLOY) increased as tissue progressed from normal to abnormal and cancerous, supporting the researchers’ hypothesis that Y-chromosome loss may play a role in cancer development.

It has already been proven that loss of Y chromosome (LOY) is associated with many types of cancer in men. However, less was known about the extent of mLOY in normal-appearing tissues from men with or without cancer and how it changes across tissue as cancer develops.

Men have one X and one Y chromosome in each cell of their body.

The Y chromosome contains genes involved in sex development, including the SRY gene, which plays a key role in initiating testis development during embryonic development.

mLOY means that the Y chromosome is missing from some cells but retained in others within the same person. It is a somatic change that occurs after conception, rather than a chromosome abnormality present in every cell from birth.

Loss of Y chromosome (LOY) is a somatic genetic change in which some cells lose their Y chromosome. It is commonly detected in blood cells of aging men, but LOY can also occur in other tissues. When only a proportion of cells lose the chromosome, the condition is called mosaic loss of Y chromosome, or mLOY. 

Previous studies showed that the loss of Y chromosomes in blood cells of elderly men is associated with short life expectancy, cancer and other disorders. 

Most previous research on mLOY has focused on blood cells, where the alteration becomes increasingly common with age and has been associated with several diseases. The new study examined whether similar Y-chromosome loss occurs within normal-appearing tissues surrounding cancer.

This study systematically profiled the loss of Y across normal, pre-cancerous and malignant tissues across 11 major human organs, including the bladder, prostate, colon, rectum, lung, pancreas and esophagus.

"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," he further added.

The study examined 1,000 tissue samples from 405 men, covering 11 organs.

They used an automated fluorescent imaging system known as Fluorescence In-situ Hybridization (FISH) to inspect more than 4.3 million individual cell nuclei.

The technique lights up the X and Y chromosome centromeres under a microscope. This allowed them to count how many cells still had a Y chromosome in a sample. Thus measuring the ratio of X to Y chromosomes.

Y Chromosome Loss Increased From Normal Tissue to Cancer

The researchers found a progressive pattern of mLOY across tissue states. Cancer-free normal tissue showed the least Y-chromosome loss, while histologically normal tissue adjacent to a tumor showed greater loss, and malignant tissue showed the greatest degree of loss. Paired analyses within the same patients also showed greater mLOY in tumors than in adjacent normal-appearing tissue.

Here, "normal-appearing" refers to tissue that appeared normal under pathological examination, even though it was located near a tumor. The researchers found that these tissues could already contain increased mLOY.

Gradient was observed across histologically normal and malignant tissues:

1. Histological sections from cancer-free tissues had the least Y-loss, tissue sitting next to a tumor (but still histologically "normal") had comparatively more Y-loss, and the actual tumor tissue had the most.

2. When comparing tumor tissue to the adjacent normal-looking tissue within the same patient, the tumor consistently showed more Y-loss.

3. In the bladder mapping, they could literally trace increasing Y-chromosome loss as tissue progressed from normal → early abnormal changes → full-blown invasive cancer.

The study examined bladder tissue to determine decreasing Y chromosomes in cells.

In one part of the study, the researchers specifically created detailed maps of bladder tissue that had been removed during cancer surgery. 

These maps helped the researchers see how Y chromosome loss increased from normal bladder tissue, to  early abnormal cells, and into full-blown cancer.

The researchers discovered that the extent of mLOY varied by cancer type. With colorectal cancer showing the greatest degree of Y-chromosome loss in the study. High levels were also observed in stomach, lung, pancreatic, head-and-neck and esophageal cancers.

The findings are consistent with a phenomenon known as field cancerization, in which apparently normal tissue surrounding a tumor can contain molecular and genetic changes associated with cancer development. In this study, increasing mLOY was observed as tissue moved closer to malignant transformation.

Could Y Chromosome Loss Help Detect Cancer Earlier?

The findings do not mean that Y-chromosome loss can currently be used as a routine cancer screening test. Instead, they provide evidence that mLOY may be detectable in tissue before cancer becomes morphologically obvious. The researchers suggest that measuring mLOY could eventually help identify abnormal tissue or biopsies that appear normal under conventional examination but may contain molecular changes associated with early cancer development.

At present, this remains a potential research application rather than an established clinical diagnostic or screening method. Further studies are needed to determine whether mLOY can reliably distinguish tissue at risk of cancer and whether it can improve early detection or patient outcomes.

What Are the Limitations of the Y Chromosome Loss Study?

The researchers relied on tissue microarrays and relatively small tissue cores, which may not capture the full heterogeneity of a tumor. In addition, tissue samples can contain different cell types, including epithelial, stromal and immune cells, which may influence measurements of Y-chromosome loss.

The study demonstrates a tissue-level association between mLOY and cancer-related changes but does not establish the sensitivity, specificity or predictive value required for a clinical cancer screening or diagnostic test.

1. Gertych, Arkadiusz, Huihui Ye, Xingyu Chen, Eric Vail, V. Krishnan Ramanujan, Lauren Brady, Lawrence D. True, et al. “Human Y Chromosome Pan-Organ Mapping Reveals Progressive Mosaic Loss from Normal to Cancer.” JCI Insight 11, no. 17 (2026): e201996. https://doi.org/10.1172/jci.insight.201996.

2. Abdel-Hafiz, Hany A., Lena Hoelzen, and Dan Theodorescu. “Beyond Sex Determination: The Y Chromosome in Male Cancers.” Nature Reviews Cancer 26 (2026): 586–603. https://doi.org/10.1038/s41568-026-00935-x.

3. Gutiérrez-Hurtado, I. A., et al. “Loss of the Y Chromosome: A Review of Molecular Mechanisms, Age Inference, and Implications for Men’s Health.” International Journal of Molecular Sciences 25, no. 8 (2024): 4230. https://doi.org/10.3390/ijms25084230.

(Rh/MF/MSM)