Gender Difference in Bladder Cancer Susceptibility

 描述（由申请人提供）：男性患膀胱癌（BCa）的可能性是女性的3-4倍。事实上，几乎所有类型的癌症的发病率在男性中始终高于女性。男性和女性之间遗传组成的关键差异是性染色体互补（XX与XY）。然而，我们不知道性染色体在多大程度上对BCa易感性的性别差异负责。我们也不知道是否性染色体增强或减少性腺激素依赖性二型表型。两性异形的表观遗传规划是一个新兴的领域。目前，对BCa易感性性别差异的表观遗传机制基本上一无所知。许多表观遗传程序调节组蛋白甲基化以维持染色质的活性或沉默状态。X连锁的组蛋白脱甲基酶Utx/Kdm 6a是一种表观遗传调节因子，在发育过程中以性别特异性方式发挥作用;该基因在超过25%的人类BCa病例中突变。此外，人类BCa中表观遗传调节因子的突变率显著高于癌症基因组图谱（TCGA）项目中研究的所有其他上皮癌。因此，X连锁，Utx依赖的表观遗传程序可能会赋予性别特异性基因表达差异，膀胱尿路上皮，从而影响BCa的易感性。为了解决上面强调的问题，我们将首先使用一种新的小鼠模型，该模型由“四个核心基因型”--XX和XY--具有卵巢的雌性，以及XY-Sry和XXSry--具有睾丸的雄性--组成，以研究BCa易感性的性别差异是否取决于性染色体补体和/或性腺类型。其次，我们将确定是否Utx依赖的表观遗传程序导致的BCa发病率的性别差异，使用小鼠条件性基因敲除（cKO）策略。第三，我们将使用基因组技术来确定性二态性的遗传和表观遗传目标的UTX依赖的表观遗传程序。这些分子特征的鉴定可能揭示BCa性别差异的潜在表观遗传机制。总之，拟议的研究将显著提高我们对BCa易感性性别差异的理解，并可能大大改变我们对癌症发病率性别差异中表观遗传编程的新兴范式的看法，并可能导致未来基于表观遗传的BCa治疗策略。

 DESCRIPTION (provided by applicant): Men are 3-4 times more likely to develop bladder cancer (BCa) than women are. In fact, the incidence of almost all types of cancer is consistently higher in males than in females. The key difference in genetic makeup between males and females is the sex chromosome complement (XX versus XY). We do not know, however, the extent to which sex chromosomes are responsible for the gender difference of BCa susceptibility. Neither do we know whether sex chromosomes enhance or reduce the gonadal hormone-dependent sexually dimorphic phenotypes. Epigenetic programming in the sexual dimorphism is an emerging field. At present, essentially nothing is known about the epigenetic mechanism of the gender difference in BCa susceptibility. Many epigenetic programs regulate histone methylation to maintain active or silent states of chromatin. The X- linked histone demethylase, Utx/Kdm6a, is an epigenetic regulator that functions in a sex-specific manner during development; this gene is mutated in over 25% of human BCa cases. Furthermore, mutation rates of epigenetic regulators are significantly higher in human BCa than all other epithelial cancers studied in The Cancer Genome Atlas (TCGA) projects. Thus, the X-linked, Utx-dependent epigenetic program may impart sex-specific gene expression differences in bladder urothelium, and consequently influence BCa susceptibility. To address questions highlighted above, we will first use a novel mouse model, which consist of the "four core genotypes"-XX and XY- females with ovaries, and XY-Sry and XXSry males with testes-to investigate whether the gender difference in BCa susceptibility depends on the sex chromosome complement and/or the gonadal types. Second, we will determine whether the Utx-dependent epigenetic program causes the sex disparity in BCa incidence using a mouse conditional knockout (cKO) strategy. Third, we will use genomic technology to identify sexually dimorphic genetic and epigenetic targets of the Utx-dependent epigenetic program. Identification of these molecular features may shed light onto the underlying epigenetic mechanism of the sex disparities of BCa. Together, the proposed studies will significantly improve our understanding of the gender difference in BCa susceptibility, and may substantially alter our view of the emerging paradigm of epigenetic programing in the sex disparities in cancer incidence, and could potentially lead to future epigenetic-based treatment strategies to BCa.