Loss Of Y Chromosome In Men Enables Cancer To Grow

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” says Professor Dan Theodorescu, the corresponding author from Cedars-Sinai Medical Center. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

The loss of the Y chromosome has also been observed in several types of diseases which includes 10-40% of bladder cancers, it is linked with cardiovascular disease and Alzheimer’s disease, and it may help to explain why women generally live longer than men. 

Biological gender is determined by chromosomes that carry our DNA, males have XY chromosomes while females have XX. The Y chromosome is one-third of the size of its counterpart, and it carries around 55 genes that are mostly to deal with being male, while the X chromosome represents about 5% of a cell's total DNA and likely contains over 900 genes that are essential for proper development and cell viability. 

The researchers are working on developing a Y chromosome test to aid in the customization of immune checkpoint-inhibiting drugs. The Y chromosome contains the blueprints for certain genes, based on the way they are expressed in normal cells within the bladder lining a scoring system was developed to measure the loss of the Y chromosome in cancers. 

Next, the researchers reviewed data from two groups of men: one group had muscle-invasive bladder cancer and had their bladders removed but were not treated with an immune checkpoint inhibitor, while the other group participated in a clinical trial and was treated with an immune checkpoint inhibitor. Those with loss of the Y chromosome were found to have a poorer prognosis in the first group and much better overall survival rates in the second group. 

To investigate why this happened the researchers compared the growth rates of bladder cells from laboratory mice.  Cancer cells were grown in a dish where the cells were not exposed to immune cells, and diseased cells were also grown in mice that were missing immune T-cells. The researchers report that in both cases, tumors with/without the Y chromosome grew at the same rate. In animals with an intact immune system tumors without the Y chromosome grew more rapidly than those with an intact Y chromosome. Based on their findings the team concluded that tumors missing the Y chromosome while being more aggressive are also more vulnerable and responsive to immune checkpoint inhibitors. 

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

"Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said Hany Abdel-Hafiz, Ph.D., associate professor at Cedars-Sinai Cancer and co-first author of the study with Schafer and Xingyu Chen, a research bioinformatician at Cedars-Sinai.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumor cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs and dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”