Study Reveals Impact of Y Chromosome Loss on Cancer Prognosis

The Y chromosome plays a crucial role in male biology, influencing everything from reproduction to immune function. However, emerging research suggests that the loss of the Y chromosome—a condition known as Y chromosome loss (LOY)—may have serious health consequences, particularly in relation to cancer. Studies indicate that men who experience LOY are more likely to suffer from aggressive forms of cancer and poorer treatment outcomes.

Researchers at Cedars-Sinai have discovered that male cancer patients whose tumor cells and immune cells both experience Y chromosome loss tend to have worse outcomes compared to those without this genetic change. Their findings, published in Nature, could pave the way for more effective cancer treatments.

The Y chromosome is one of the two chromosomes that determine biological sex in mammals. While females possess two X chromosomes, males have one X and one Y. As men age, it is common for them to lose the Y chromosome in some cells.

A 2023 Cedars-Sinai study revealed that Y chromosome loss in bladder cancer cells helped these cells evade the body's immune system, enabling tumor growth. However, tumors lacking the Y chromosome were also more responsive to immune checkpoint therapy than those with an intact Y chromosome.

Building on previous research highlighting the challenges posed by Y chromosome loss in male tumors, co-senior authors Simon Knott, PhD, assistant professor of Biomedical Sciences at Cedars-Sinai, and Dan Theodorescu, MD, PhD, sought to explore its effects in other cancer types.

By analyzing large public datasets, the study examined Y chromosome loss across various cancers. Surprisingly, researchers found that not only cancer cells but also multiple cell types associated with tumors exhibited this genetic alteration, leading to further investigations.

Ties Between Immune and Cancer Cells

"Losing the Y chromosome in both these cell types at once correlated with hyperaggressive cancer cells and malfunctioning immune cells that are meant to attack the cancer cells. This creates an aggressive tumor with very poor outcomes."

Beyond analyzing cancer databases, researchers validated their findings by examining Y chromosome loss in patient tumor samples and conducting preclinical studies using specialized techniques. These additional methods confirmed their observations.

T-cell Therapies and LOY

The results may also have implications for patients undergoing T-cell therapies. In these treatments, immune cells—known as T-cells—are extracted from the patient, modified in the laboratory to enhance their ability to combat cancer, and then reintroduced into the body.

T-cells lacking the Y chromosome may be less capable of executing immune responses, reducing the effectiveness of therapies based on them.

Additional studies are necessary to help researchers determine the most effective ways to adjust these therapies to accommodate Y chromosome loss.

What Is Y Chromosome Loss?

LOY occurs when cells gradually lose the Y chromosome, a phenomenon observed in aging males. While this genetic loss was once thought to be harmless, recent studies suggest that it can contribute to various health risks, including reduced immune response, increased inflammation, and a greater susceptibility to diseases such as Alzheimer's and cardiovascular conditions.

The Link Between LOY and Cancer

Recent research has shown that LOY can significantly impact cancer progression. Without the Y chromosome, certain immune cells struggle to fight off cancerous growths effectively. This weakened immune response makes tumors more resistant to treatment and increases the likelihood of severe disease.

For example, studies have found that men with LOY in their blood cells are more prone to aggressive prostate, lung, and bladder cancers. Additionally, their bodies may not respond as well to immunotherapy, a common cancer treatment designed to activate the immune system against tumors.

Why Does LOY Happen?

LOY is often linked to aging, smoking, and other environmental factors. As men grow older, their cells naturally undergo genetic changes, sometimes resulting in Y chromosome loss. Lifestyle choices, such as smoking, can accelerate this process, further increasing cancer risk.

Potential Solutions and Future Research

Scientists are exploring ways to counteract LOY’s impact on cancer treatment. Some researchers believe that identifying LOY early could help personalize therapies for affected individuals, improving outcomes. There is also growing interest in using gene-editing techniques and targeted medications to restore immune function in men with LOY.

Final Thoughts

While Y chromosome loss may seem like a minor genetic change, its impact on cancer outcomes is significant. Understanding how LOY affects the immune system and cancer progression could lead to better treatments and preventative measures, ultimately improving survival rates for men at risk. As research continues, experts hope to find new ways to combat the negative effects of Y chromosome loss and enhance cancer therapies.

References:

1. Dirican, Canan D., and Peter S. Nelson. "Y chromosome loss and implications for oncology." Molecular Cancer Research 22, no. 7 (2024): 603-612.
   https://aacrjournals.org/mcr/article/22/7/603/746054

2. McGranahan, Nicholas, and Rahul Roychoudhuri. "Y-chromosome loss in cancer and immune cells might worsen treatment outcomes." (2025).
   https://www.nature.com/articles/d41586-025-01450-z

(Rehash/Mradula U Naik/MSM)