Loss of the Y Chromosome in Men and Its Striking Link to Cancer
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Scientists have found that a common consequence of aging in men, loss of the Y chromosome, may help cancer cells escape the body’s immune system and lead to aggressive bladder cancer. Yet it may also make the disease more sensitive to therapies known as immune checkpoint inhibitors, a type of immunotherapy. These findings were reported in a recent study published on 21 June 2023 in Nature by Abdel-Hafiz and colleagues.
The Y chromosome is a primary factor determining an individual’s biological sex. In humans, females have two X chromosomes, while males have one X and one Y chromosome. The Y chromosome contains genes that determine the development and phenotype (physical characteristics) of male sexual traits. For example, the SRY gene on the Y chromosome is a determining factor in male sexual development. The Y chromosome generally contains few genes. While the X chromosome contains thousands, the Y chromosome has only 50-60 genes. However, many of these genes are thought to be associated with numerous sex-related diseases, particularly in males. The Y chromosome is also important for tracking genetic haplotypes and for evolutionary genetic studies. It is passed from father to son and generally remains unchanged, making it useful for tracing genetic ancestry and migration.
Why the Study Matters
Given the complexity of cellular mechanisms and genetic factors, advances in cancer treatment often come in small steps. However, this study provides an important breakthrough in understanding how loss of the Y chromosome in men may help cancer cells evade the body’s immune system and thus affect treatment sensitivity. A better understanding of such genetic changes and their effects on cancer treatment is necessary to develop more effective treatment approaches.
What Was Known Before This Study
As men age, some cells lose their Y chromosome, which may impair the body’s ability to fight cancer. Y-chromosome loss has been observed in cardiovascular disease, Alzheimer’s disease and bladder cancers, in 10% to 40% of cases.
Immunotherapies in the immune checkpoint inhibitor class, a key approach to bladder cancer treatment, can reactivate T cells to help the body fight cancer.
This study establishes a previously unexplored link between Y-chromosome loss and the immune response to cancer. The research team discovered that loss of the Y chromosome allows bladder cancer cells to evade the immune system and grow very aggressively.
Although female patients do not have a Y chromosome, these new findings may also have implications for them. The Y chromosome contains a set of genes with counterparts on the X chromosome, known as paralogous genes, which may play a role in both females and males.
Paralogous genes are genes within the same species’ genome that arose through evolutionary duplication of a gene. In other words, a gene was once duplicated, and the duplicated version changed over time to acquire a different function. They generally have similar, but not identical, functions.
The meaning of this statement about the Y chromosome needs further explanation. Most genes on the human Y chromosome have counterparts on the X chromosome. These counterparts are generally paralogous genes, present on both the X and Y chromosomes in males.
However, because females have two X chromosomes while males have one X and one Y chromosome, loss of genes from the male Y chromosome may have genetic and biological effects that paralogous genes on the X chromosome generally cannot compensate for. This illustrates how a particular genetic change can have different effects in males and females. Because females lack a Y chromosome, loss of its genes has no direct effect on them, but similar genetic processes or diseases may act through paralogous genes on the X chromosome.
The underlying idea is that Y-chromosome loss and its effects on the immune system might also have biological implications for females, perhaps through interactions involving paralogous genes on the X chromosome. However, this remains an unresolved area of genetic research. Any suggested effect of the Y chromosome in females may therefore occur in very specific and perhaps unexpected ways.
Bladder cancer is approximately 3-4 times more common in men than in women. The study discussed here suggests that loss of the Y chromosome contributes to bladder cancer being more common in men.
Study Results
The Y chromosome contains the “instruction sets,” or blueprints, for particular genes. The term blueprint generally means a plan or model. In biological terms, each gene is like a blueprint or set of instructions determining the structure and function of a protein or another genetic product.
The researchers closely examined how these genes are expressed in normal cells lining the bladder. From this analysis, they developed a scoring system to identify Y-chromosome loss in tumors and help personalize treatment for male bladder cancer patients. The system could help tailor and manage responses to immune checkpoint inhibitors more effectively.
The researchers then examined data from two patient groups:
- male patients with muscle-invasive bladder cancer (spread into the muscle layer) who had undergone cystectomy (surgical bladder removal) but had not received immune checkpoint inhibitors; and
- patients enrolled in a clinical trial who received immune checkpoint inhibitors.
They found that patients with Y-chromosome loss had a worse disease course in the first group and much better overall survival rates in the second.
To determine why, the researchers compared bladder cancer-cell growth rates using laboratory mice. They grew cancer cells in a dish without exposure to immune cells and in mice lacking T cells. In both settings, tumors with and without the Y chromosome grew at the same rate. In mice with intact immune systems, tumors lacking the Y chromosome grew much faster than those with it. This suggested that Y-chromosome loss helps cells evade the immune system.
The difference in growth rate when the immune system is involved is key to the “Y-loss” effect in bladder cancer. These results show that when cells lose the Y chromosome, they exhaust T cells; without T cells to fight the cancer, the tumor grows aggressively.
Preliminary data from another, as yet unpublished study suggest that loss of the Y chromosome may also make prostate cancers more aggressive.
How Is Y-Chromosome Loss Measured?
In this study, Y-chromosome loss was measured using techniques such as genetic and transcriptomic studies, flow-cytometric analyses, single-nucleus RNA sequencing and spatial proteomic assessment. These are common biomedical research methods for measuring changes at the genetic and protein levels.
This study suggests that Y-chromosome loss could be used, particularly for sensitivity to immunotherapy, as a biomarker for treatment response. However, more research and further studies are needed to realize this potential
In conclusion, we believe that loss of the Y chromosome is an adaptive strategy developed by tumor cells to evade the immune system and survive in multiple organs. This exciting advance contributes to our fundamental understanding of cancer biology and could have far-reaching implications for cancer treatment in the future.
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