Tracking mysteries of loss of Y chromosome, cancer

The Y chromosome is among the smallest in the human body and carries the fewest genes. Researchers are paying renewed attention to its role in cancer — specifically, what happens when it vanishes. 

Women typically have two X chromosomes, and men an X and a Y. Men generally face a higher cancer risk than women in most shared anatomy, with the biggest differences in bladder, gastric cardia, and larynx disease. Researchers think lifestyle factors, such as diet, exercise, and exposure to carcinogens, explain some of the disparity, but not all.

Recent evidence suggests the disappearance of the Y chromosome in tumor cells may explain some of the gender gap in some cancer types, like kidney cancer. Understanding the connection could eventually lead to new therapies.

The gradual loss of the Y isn’t unusual. By the time they’re 70 years old, about 40 percent of men have lost at least some of the Y chromosome in their blood cells. In addition, the chromosome is frequently lost in tumors.

The Y chromosome primarily carries genes that provide instructions for male sex differentiation and fertility. But it also carries some known to suppress tumor growth — a protective ability that is lost if those genes are damaged or destroyed.

Luis Antonio Corchete Sánchez, a postdoctoral research fellow at the Krantz Family Center for Cancer Research at Mass General Brigham Cancer Institute and co-author of a recent review article on the issue in the journal Trends in Cancer, likens Y-chromosome gene loss to library books sent through a paper shredder: “You’ve lost those books forever; you can never recover that information,” he said. 

Loss of the Y chromosome, or LOY, in tumors is a separate process from aging-related LOY, said Esther Rheinbay, Corchete Sánchez’s co-author. About 30 percent of primary tumors in men harbor either complete or partial LOY. In papillary renal cell carcinoma, a type of kidney cancer, the rates may be as high as 80 percent. 

But the causality is far from clear. Scientists don’t know whether LOY causes tumors to grow, or whether LOY and tumor growth both result from some third process. The answer may vary by type of cancer, or even by individual patient. 

“We know, at least in some tumor types, Y chromosome loss occurs very early in tumor evolution, but probably along with other alterations,” said Rheinbay, an assistant professor at Harvard Medical School and principal investigator at the Krantz Family Center. “One thing we’re trying to understand is: What’s the order of events? Is [LOY] oncogenic on its own, or does it need collaborators? That’s something we simply don’t know yet.” 

“Every time we find more insight into the loss of the Y chromosome, we find more questions and more potential research gaps,” said Corchete Sánchez. 

Studies of people with less common chromosome patterns, like males with an extra X chromosome or females missing or partly missing an X chromosome, suggest that X chromosomes may offer some protection against solid tumors, while the presence of a Y chromosome is associated with greater cancer risk.

But the little chromosome has proven frustratingly difficult to study.

“The Y chromosome is really rich in repetitive regions, so it’s hard to decide where the signal is coming from,” Rheinbay explained. “Together with the fact that it’s small, and there are very few genes relevant for cancer, it’s been deprioritized in analysis.”

Rheinbay’s team has been developing specialized tools to better define the status of the Y chromosome in cancer.

The same peculiarities that make the Y chromosome hard to study also offer promising opportunities for new cancer therapies. 

“LOY in cancer cells leads to this exposed X chromosome,” Rheinbay said. “Because that doesn’t happen in most other cells, there’s a therapeutic window where we can potentially treat those cancer cells, and they will be way more sensitive to the drug than the normal cells with Y chromosome. That’s what we want: a treatment that kills the cancer but doesn’t hurt normal cells.”

“It’s exciting to venture into an area that has not been explored,” added Rheinbay. “And always thinking about the impact we could have on patient treatment makes it very exciting and very motivating.”