October 2023 | George M. Pikler, M.D., Ph.D., FACP

Y Chromosome Is a Troublemaker

A long-standing question in the cancer field has been why men have a higher overall cancer incidence associated with poorer outcomes than women. The Y chromosome could explain why some cancers are more deadly in men and others who carry the chromosome.

Now two independent studies published in Nature have collectively addressed this question of sex bias in cancer and implicated the Y chromosome in aggressive features of colorectal and bladder cancers in men.

One study (1) found that losing the Y chromosome naturally through age, or through CRISPR–Cas9 gene editing, could make bladder cancer more aggressive. Of note, compared with Y+ tumors, Y− tumors exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy.

Another study (2) found that a gene located on the Y chromosome, KDM5D, promoted the metastatic spread of colorectal cancer.

These two studies provide the first examples of sex-specific mechanisms involving non-hormonal genes of the Y chromosome in producing cancer disparities.

Many cancers are worse in men than in women, and these studies suggest that genetic factors, rather than just lifestyle, could be responsible, says cancer researcher Sue Haupt. But, because the Y chromosome has a protective effect in one cancer and a harmful effect in another, “you cannot generalize”, says Haupt. “When people just throw all the data together, they miss the point.”

(1) Nature (2023) 619: 624-631 (2) Nature (2023) 619: 632-639