Gender Difference in Bladder Cancer Susceptibility

 描述(由申请人提供)：男性患膀胱癌的可能性是女性的3-4倍。事实上，几乎所有类型的癌症在男性中的发病率始终高于女性。男性和女性在基因构成上的关键区别是性染色体的组成(XX对XY)。然而，我们不知道性染色体在多大程度上导致了BCA易感性的性别差异。我们也不知道性染色体是增强还是减少性腺激素依赖的性二型性表型。性二型性的表观遗传编程是一个新兴的领域。目前，对于BCA易感性的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跃或沉默状态。X连锁的组蛋白去甲基酶UTX/Kdm6a是一种表观遗传调节因子，在发育过程中以性别特异性的方式发挥作用；该基因在超过25%的人类BCA病例中发生突变。此外，在人类BCA中，表观遗传调节因子的突变率明显高于癌症基因组图谱(TCGA)项目中研究的所有其他上皮性癌症。因此，X连锁的、UTX依赖的表观遗传程序可能导致膀胱尿路上皮中性别特异的基因表达差异，从而影响BCA的易感性。为了解决上述问题，我们将首先使用一个新的小鼠模型，该模型由四个核心基因型-XX和XY-雌性卵巢，以及XY-Sry和XXSry雄性睾丸-来调查BCA易感性的性别差异是否取决于性染色体和/或性腺类型。其次，我们将使用小鼠条件基因敲除(CKO)策略来确定UTX依赖的表观遗传程序是否会导致BCA发病率的性别差异。第三，我们将使用基因组技术来确定UTX依赖的表观遗传计划的性二态遗传和表观遗传目标。这些分子特征的鉴定可能有助于揭示BCA性别差异的潜在表观遗传学机制。总之，拟议的研究将显著提高我们对BCA易感性的性别差异的理解，并可能极大地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，并可能潜在地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.