A new paper published in Nature on June 4 shines light on how an enigmatic part of male aging—the loss of Y chromosomes—is connected with a higher risk of dying from cancer.
In an analysis of 4,127 tumors across 29 cancer types—including colon cancer, brain cancer, lung cancer, leukemia and lymphoma—patients with tumors that had lost the Y chromosome suffered worse survival outcomes than patients whose tumors still had the chromosome.
What’s more, the researchers found through experiments that Y-less cancer cells can somehow cause other cells in the tumor microenvironment, like T cells and fibroblasts, to also lose the Y chromosome. The loss of Y from T cells is further associated with even worse survival in cancer patients, according to the researchers.
The findings have “very broad ramifications, because they basically impact half of the population,” Dan Theodorescu, M.D., Ph.D., director of the University of Arizona Cancer Center and senior author of the study, told Fierce Biotech in an interview. “We are in a totally new realm of biology.”
“The strong prediction from this paper is that T cells without the Y chromosome will be not as effective at rejecting tumors, and likely be less sensitive to checkpoint inhibitors,” Theodorescu added.
This means that doctors should weigh the Y chromosome status of a patient’s cancer before deciding on treatment options that leverage the immune system, he elaborated, such as autologous CAR-T therapies.
“The study highlights the potential value of assessing Y-chromosome status in the tumor microenvironment, not just in cancer cells, when considering patient prognosis and potential treatment approaches,” oncologists Nicholas McGranahan, Ph.D., of University College London, and Rahul Roychoudhuri, Ph.D., of the University of Cambridge, wrote in a related commentary piece, also published in Nature on June 4.
It's been known since at least the 1960s that blood cells tend to lose Y chromosomes as men age, but the fact that this chromosomal disappearing act is associated with a shorter lifespan, higher cancer risk and worse cancer outcomes wasn’t appreciated until about 10 years ago. Theodorescu’s research group then found in a 2023 paper that losing Y helps tumors evade the immune system.
All in all, about 2.5% of 40-year-old men, 40% of 70-year-old men and 57% of 93-year-old men have some blood cells that have lost the Y chromosome.
Theodorescu is now focused on trying to understand how Y-less cancer cells can spread their chromosomal loss to other cells, and whether or not Y-less tumors serve as magnets that attract Y-less cells from elsewhere in the body.
Another big unknown is the full extent of Y chromosome loss that occurs in men as they age, and what the other health implications may be. In addition to cancer, the loss of Y is also known to be linked to higher risks of Alzheimer’s and cardiovascular diseases.
Though scientists know Y loss happens in blood cells, whether Ys are also dropped from other dividing cells in the body is unclear, though Theodorescu said he wouldn’t be surprised if that’s the case.
“I would be shocked if it was only in the blood cells,” he said.
Theodorescu’s ultimate goal is to piece together how the Y chromosome is lost on a basic level so that it can be prevented.
“I want to get to a therapeutic in the end,” he said. “We take Lipitor so we don't get cardiac events, maybe at age 40 you should be taking something so you don't lose your Y chromosome.”