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NatureHow the Y chromosome makessome cancers more deadly for men
Two studies help to explain why colorectal and bladder tumors take a bigger toll on men
than on women.

Figure. Colon cancer (pictured) is one of several types of cancer that has more severe

Colon cancer

effects on men than women.Credit: Steve Gschmeissner/Science Photo Library.
The Y chromosome could explain why men are less likely than women to survive somecancers, according to studies that combine data from mice and humans.
Two studies, both published on 21 June in Nature, address cancers that are particularly
aggressive in men: colorectal cancer and bladder cancer. One study finds that the loss ofthe entire Y chromosome in some cells

which occurs naturally as men age

raises therisk of aggressive bladder cancer and could allow bladder tumors to evade detection by the evade detection by theimmune system. The other finds that a particular Y-chromosome gene in mice raises theimmune systemrisk of some colorectal cancers spreading to other parts of the body.
Taken together, the two studies are a step towards understanding why so many cancers
have a bias towards men, says Sue Haupt, a cancer researcher at the George Institute of
Global Health in Sydney, Australia, who was not involved with the work.

Not just lifestyleLifestyle has long been given the blame for the fact that many non-reproductive cancers
tend to be more frequent and more aggressive in men than women. Men are more likely tosmoke and drink alcohol, for example. But even when such factors are accounted for, somedifferences in cancer rate or severity between men and women persist.

reproductivewhile recognizing that
not all people who identify as men have a Y chromosome, and not all people who havea Y chromosome identify as men.)
Meanwhile, researchers have also found that the Y chromosome, which is often found inmen, can be spontaneously lost during cell division. As men age, the proportion of Y-lessblood cells increases, and an abundance of such cells has been linked to conditions
including heart disease, neurodegenerative conditions and some cancers.
To learn more about how this process might affect bladder cancer
biasa cancer with a male

Dan Theodorescu, a cancer researcher at Cedars-Sinai Medical Center in Los

Angeles, California, and his colleagues studied human bladder cancer cells that had either
lost their Y chromosome spontaneously, or had it removed using CRISPR Cas9 genome
editing.
The team found that such cancer cells were more aggressive when transplanted into micethan comparable cells that still had their Y chromosome. They also found that immune cells
surrounding tumors with no Y chromosomes tended to be dysfunctional.
In mice, a therapeutic antibody that can restore the activity of those immune cells wasmore effective against such Y-less tumors than against tumors that still had their Ychromosome. The team found a similar trend in human tumors. This finding isof the study, says Jan Dumanski, a geneticist at Uppsala University in
Sweden who was not involved with the research, because it suggests a better way to treat
these cancers. Similar antibodies, called checkpoint inhibitors, are already used clinicallyagainst some tumors.
Risk from the Y chromosome
In a separate study, a team working on colorectal cancer in mice found that a gene on theY chromosome called KDM5D might weaken connections between tumor cells, helping
the cells to break away and spread to other parts of the body. When that gene was deleted,tumor cells became less invasive, and were more likely to be recognized by immune cells.
This also presents a potential target for anti-cancer therapies, says co-author RonaldDePinho, a cancer researcher at the University of Texas MD Anderson Cancer Center in
The contrast between the two findings

a protective role for the Y chromosome inbladder cancer and a harmful role for a Y-chromosome gene in colorectal cancer
emphasizes the importance of context in cancer, says Theodorescu.
he says, and researchers will need to lookat the effect of losing the Y chromosome on various organs and tumor types.

location in the organ and the presence or absence of other genetic mutations, says Haupt.

Nature 618, 898 (2023)
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