New research helps explain why men are three to five times more likely to develop bladder cancer than women.
Using mouse models and human patient data, Boston Children’s Hospital researchers in the urology department, Xue Sean Li, PhD, and Satoshi Kaneko, PhD, found that inherent genomic differences contribute to the contrast in bladder cancer rate between males and females. Li and Kaneko were the senior and first authors, respectively, on a new paper about the findings in Science Advances.
Li and Kaneko started out 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 (male) or XX (female) 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.
Genomic versus hormonal sex
In the Li lab, the 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.
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.
A new gene implication for bladder cancer?
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 on or off or transiently turning on and 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 knockout of the gene in urothelial cells increases bladder cancer risk in mice. Together, these findings suggest that KDM6A functions as a tumor suppressor in bladder cancer.
With these mouse model findings in hand, Li and Kaneko then wondered if there was any evidence of KDM6A having influence on 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 females than in males. Moreover, female patients with lower levels of KDM6A — or with genetic mutations that disrupted the normal expression of KDM6A — had much poorer survival outcomes than females 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,” says Li, who is a principal investigator in the urology department at Boston Children’sand an assistant professor of surgery at Harvard Medical School.
Taken altogether, Li and Kaneko’s findings provide new insight into disparities in cancer risk and mortality between males and females, and 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.
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