Bladder Cancer Contrast

Getting to the root of sex-based differences in disease risk

cross-sections of orange-stained spheres

A microscopic view of human testis tissue. A new study helps explain why men are more likely to get bladder cancer than women. Image: defun/iStock

New research helps explain why men are three to five times more likely to develop bladder cancer than women.

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(For the purposes of this study, “male” was defined as having XY chromosomes and testes, and “female” was defined as having XX chromosomes and ovaries.)

Using mouse models and human patient data, researchers at Harvard Medical School and Boston Children’s Hospital found that inherent genomic differences contribute to the contrast in bladder cancer rate between the sexes.

Xue Sean Li, HMS associate professor of surgery at Boston Children’s, and Satoshi Kaneko, HMS research associate in surgery at Boston Children’s, were the senior and first authors, respectively, on the recent study, published in Science Advances.

Genomic versus hormonal sex

Li and Kaneko started by uncoupling the genomic and hormonal components of sex in a mouse model of bladder cancer.

Typically, a mammal’s genomic sex is determined by whether an individual is born with XY or XX chromosomes. The hormonal component of sex relates to whether an individual develops testes or ovaries, the reproductive organs that produce sex-specific hormones.

In nature, mammals are usually born with either XX chromosomes and ovaries or XY chromosomes and testes.

Li’s team used genetic engineering to decouple these pairings into four types of mice: XX chromosome with ovaries, XX chromosome with testes, XY chromosome with ovaries and XY chromosome with testes. This allowed the researchers to evaluate the independent roles that the genome and sex hormones play on bladder cancer risk.

Over a period of 280 days, they found that mice with XY chromosomes—even those with ovaries instead of testes—were much more likely to develop and die from bladder cancer than their XX counterparts.

Strikingly, mice born with testes, regardless of being XX or XY individuals, were even more likely to die.

A new gene implication for bladder cancer?

To better understand the genetic mechanisms behind these stark observations, Li and Kaneko decided to sequence urothelial cells, which line the urinary tract and are the most common source of bladder cancer, from the four groups of mice.

They landed an interesting genetic hit.

Expression of an X-chromosome-linked gene called KDM6A stuck out from the pack as a key differentiator between XY and XX urothelial cells, regardless of whether the mice had ovaries or testes. They found much more KDM6A expression in individuals with XX chromosomes.

In humans, KDM6A is a known factor in some breast cancers but seems to suppress tumor growth in T cell acute lymphoblastic leukemia.

Li and Kaneko then tested bladder cancer cells to see if expression of KDM6A—either constantly or transiently on or off—would influence the ability of the cancer cells to proliferate over time.

They found that constant expression of KDM6A significantly repressed cell growth. Moreover, they found that knocking out the gene in urothelial cells increased bladder cancer risk in mice.

Together, these findings suggest that KDM6A functions as a tumor suppressor in bladder cancer, the authors said.

With these mouse model findings in hand, Li and Kaneko then wondered if there was any evidence of KDM6A influencing the outcomes of human patients with bladder cancer.

Finding a hit in clinical data

By searching genomic and clinical data from The Cancer Genome Atlas, they found that KDM6A expression was much higher in women than in men. Moreover, women with lower levels of KDM6A—or with genetic mutations that disrupted the normal expression of KDM6A—had much poorer survival outcomes than women with normal levels of KDM6A expression.

“We have found that the X chromosome offers protection from bladder cancer and that X-linked KDM6A confers additional benefit by acting as a tumor suppressor,” said Li, who is a principal investigator in the urology department at Boston Children’s.

Taken altogether, Li and Kaneko’s findings provide new insight into sex-based disparities in cancer risk and mortality. They further suggest that X-chromosome-linked KDM6A is potential new biomarker that can predict prognosis for patients with bladder cancer and could even set the stage for future therapies.

This work was supported by the National Cancer Institute of the National Institutes of Health (1R21CA198544).

Adapted from a post on Vector, the Boston Children’s research and clinical innovation blog.