Loss of Y chromosome in aging men fuels cancer: study

By Mark Waghorn via SWNS

Loss of the Y chromosome as men age fuels cancer, according to new research.

It commonly disappears from blood cells as they get older enabling tumors to grow. The phenomenon affects an estimated four in ten 70-year-olds.

The discovery could lead to personalized treatments for bladder cancer, say scientists.

Corresponding author Professor Dan Theodorescu, of Cedars-Sinai medical Center, Los Angeles, said: "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.

"We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively."

It has been observed in several types of the disease, including up to 40 percent of bladder cancers.

Loss of the Y chromosome is also linked with cardiovascular disease and Alzheimer's. It may help explain why women have greater longevity.

The US team is now developing a Y chromosome test with the goal of helping tailor drugs called immune checkpoint inhibitors.

A child's gender is determined by chromosomes - known as X and Y. They carry our DNA. Males have XY, while females have XX.

Fathers contribute the X or Y, and mothers an X. Inherit an X and Y and you are a boy.

The Y chromosome contains the blueprints for certain genes.

Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.

They then reviewed data on 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.

The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor.

They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

Experiments in male mice also found tumors lacking the Y chromosome grew at a much faster rate.

Theodorescu said: "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.

"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."

T-cells are a type of white blood cell that help fight cancer. Tumors missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors.

This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body's immune system to fight the cancer.

Co-first author Professor Hany Abdel-Hafiz, also from Cedars-Sinai, said: "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."

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

Professor Shlomo Melmed, dean of the Medical Faculty at Cedars-Sinai, said: "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.

"This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward."

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

Theodorescu said: "If we could understand those mechanics, we could prevent T-cell exhaustion.

"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."

The study in the journal Nature could even have implications for women - even though they don't carry the Y chromosome.

It contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

Theodorescu said: "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.

“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.”