Researchers at Harvard University are investigating the role of the Y chromosome in cancer, particularly focusing on what happens when this chromosome is lost in tumor cells. The Y chromosome is one of the smallest in humans and contains few genes, mainly those responsible for male sex differentiation and fertility. However, it also includes genes that can suppress tumor growth.
Men have a higher risk of developing certain cancers compared to women, especially in organs like the bladder, gastric cardia, and larynx. While lifestyle factors such as diet and exposure to carcinogens contribute to this disparity, recent studies suggest that the loss of the Y chromosome (LOY) may also play a role.
By age 70, about 40 percent of men have experienced some loss of the Y chromosome in their blood cells. This phenomenon is even more common in tumors. According to Luis Antonio Corchete Sánchez, a postdoctoral research fellow at Mass General Brigham Cancer Institute and co-author of a review article published in Trends in Cancer, losing these genes is like “You’ve lost those books forever; you can never recover that information.”
Esther Rheinbay, assistant professor at Harvard Medical School and principal investigator at the Krantz Family Center for Cancer Research, noted that LOY in tumors is distinct from aging-related LOY. She said about 30 percent of primary tumors in men show complete or partial LOY, with rates reaching up to 80 percent in papillary renal cell carcinoma.
The relationship between LOY and cancer development remains unclear. Scientists are still determining whether LOY causes tumor growth or if both result from another process. “We know, at least in some tumor types, Y chromosome loss occurs very early in tumor evolution, but probably along with other alterations,” Rheinbay said. “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.”
Corchete Sánchez added: “Every time we find more insight into the loss of the Y chromosome, we find more questions and more potential research gaps.”
Studies involving individuals with atypical chromosomal patterns indicate that having extra X chromosomes may provide protection against solid tumors while possessing a Y chromosome could increase cancer risk.
Research into the Y chromosome has been challenging due to its small size and repetitive regions. “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.” Her team has developed specialized tools aimed at better understanding its status within cancer cells.
Despite these challenges, researchers see opportunities for new therapies targeting cancer cells lacking a functional Y chromosome. “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.”
Rheinbay expressed optimism about future discoveries: “It’s exciting to venture into an area that has not been explored,” she said. “And always thinking about the impact we could have on patient treatment makes it very exciting and very motivating.”
