Females have two copies of the X chromosome, while males have one X and one Y chromosome. To compensate for the extra set of X related genes in females, a process called X chromosome inactivation (XCI) occurs. This process, however, is not fool-proof and certain genes "escape" X chromosome inactivation—leading to two functional copies of the "escapee" gene in females and only one in males. If an escapee were a tumor suppressor, females would have an extra copy of the gene to provide a tumor protective advantage over males.
With increasing age, males are also susceptible to loss of Y (LOY) in which the Y chromosome and its genes lose their functions. We found that while loss of Y is linked to worse prognoses in men with bladder cancer, the condition also makes tumors more responsive to immunotherapies. Read more here. Collectively, these phenomena resulting in genetic imbalances from sex chromosomes may contribute to sex differences in bladder cancer.
Sex chromosomes have been historically overlooked for their sex-biasing functions, because many thought that sex-biasing effects stemmed from sex hormones alone. In 2008, an epidemiological study revealed that Turner syndrome patients—phenotypic females with a partially or completely absent X chromosome (i.e., XO)—had higher BC risk than XX females (1). Similarly, Klinefelter’s patients—phenotypic males with one or more extra X chromosome(s) (e.g., XXY)—had lower risk of solid tumors than XY males (2), suggesting that the X chromosome may exhibit tumor protecting behavior independent of sex hormones.
Using “four-core genotypes (FCG)” mice—mice with four sex types: two testes-bearing types with either XX or XY and two ovaries-bearing types with either XX or XY—we showed that sex chromosomes increased BC risk independently of sex hormones (3). Intriguingly, we also uncovered an interactive effect between sex hormones and sex chromosomes, observing their combined hazard ratio to be equivalent to the product rather than sum of their individual hazard ratios. The findings suggested, for the first time, that there is a potential synergistic interaction between sex hormones and sex chromosomes to amplify sex differences in BC.
We then identified KDM6A, an epigenetic regulator prone to XCI, as a prototypical female-biased bladder tumor suppressor (3). Deletion of KDM6A significantly increased BC risk in female, effectively reducing the baseline male-to-female BC risk ratio by more than five-fold. Our current research efforts aims to identify a KDM6A male counterpart gene on the Y chromosome and determine whether LOY could result in the loss of this tumor suppressor and result in an increased male BC risk. We also want to further explore how epigenetics is playing a role in this story.
1) Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA, Group UKCC. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. The Lancet Oncology. 2008;9(3):239-46.
2) Ji J, Zoller B, Sundquist J, Sundquist K. Risk of solid tumors and hematological malignancy in persons with Turner and Klinefelter syndromes: A national cohort study. Int J Cancer. 2016;139(4):754-8.
3) Kaneko S, Li X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci Adv. 2018;4(6):eaar5598.