The role of X chromosome inactivation in ovarian cancer

X染色体失活(XCI)发生在雌性发育早期，两个X染色体中的一个 染色体通过DNA甲基化转录沉默，以平衡X连锁基因的表达 男性。XCI导致雌性特有的表观基因组变异，其中不活跃的X的身份与 组织到组织，细胞到细胞，但X染色体上的一些基因实际上逃脱了失活 (‘逃逸基因’)，这两个等位基因都被转录。因为X染色体含有过多的性行为 生殖相关基因、XCI异常可能影响女性特异性骨质疏松症的发生和进展 癌症，其发病通常发生在围绝经期和绝经期后。事实上，不活跃的X一直是 据报道，XCI在卵巢癌中丢失，并且XCI的过程被证明是非随机的 卵巢癌患者的淋巴细胞，特别是BRCA突变携带者。然而，染色体- 卵巢肿瘤和未受影响组织中的广泛和基因水平的模式尚不清楚。此外， 以前的分析方法没有有效地集成多种相关的分子数据类型 需要解决XCI的“逃逸”状态。使用新颖、创新的方法来整合基因组、 需要甲基组和转录组数据来全面描述XCI图谱并评估 它们在疾病中的作用。这个项目填补了关于XCI和卵巢癌的关键知识空白 全面的多组数据集成方法，包括DNA甲基化、基因、RNA表达、 和结构变量数据。我们的主要假设是XCI的异常中断，如XCI的丢失 或在意想不到的位置失活，通过癌基因的重新激活或去激活促进肿瘤的形成 肿瘤抑制基因。我们将通过利用独特的样本资源来研究这一假设 卵巢癌患者具有丰富的基因组数据，结合来自未受影响的卵巢组织的数据。我们会 确定染色体范围的XCI模式，并识别在正常人群中首先经历和逃脱XCI的基因 卵巢组织。然后，我们将确定卵巢肿瘤中与正常相比不同于XCI的基因 并确定卵巢肿瘤中染色体范围的XCI模式是否与临床相关 各种因素。XCI在癌症研究中的作用是一个研究不足的领域，这个项目最具代表性 到目前为止，卵巢组织中XCI的综合特征。我们将更好地了解这些部位的肿瘤 并建立XCI模式的可变性和临床相关性的程度，并告知未来 研究XCI在肿瘤发生和疾病结局中的作用。值得注意的是，确定患者的XCI的能力 如果与临床特征和结果相关，简档可能会导致个体化药物的进步 已经成立了。此外，本文开发的综合XCI方法将具有更广泛的实用价值 其他女性特有的癌症或在发病率、进展或结果上表现出性别差异的癌症。

X chromosome inactivation (XCI) occurs in females early in development, where one of the two X chromosomes is transcriptionally silenced via DNA methylation to equalize X-linked gene expression with males. XCI results in epigenomic variability unique to females, where the identity of the inactive X varies from tissue to tissue and cell to cell, but some of the genes on the X chromosome actually escape inactivation (‘escapee genes’) and both alleles are transcribed. Because the X chromosome contains an excess of sex and reproductive-related genes, XCI aberrations may impact the incidence and progression of female-specific cancers, where onset is often during the peri- and post-menopausal period. In fact, the inactive X has been reported to be lost in ovarian cancer, and the process of XCI has been shown to be non-random in lymphocytes of ovarian cancer patients, particularly in BRCA mutation carriers. However, the chromosome- wide and gene-level patterns in both ovarian tumors and unaffected tissue are unknown. Furthermore, previous analysis approaches have not effectively integrated the multiple relevant molecular data types necessary to resolve XCI ‘escapee’ status. The use of novel, innovative methods to integrate genomic, methylomic, and transcriptomic data are required to comprehensively characterize XCI profiles and evaluate their role in disease. This project fills a critical knowledge gap about XCI and ovarian cancer by using a comprehensive multi-omic data integration approach, including DNA methylation, genotype, RNA expression, and structural variant data. Our overarching hypothesis is that abnormal disruption of XCI, such as loss of XCI or inactivation at unexpected loci, promotes tumorigenesis through re-activation of oncogenes or de-activation of tumor suppressor genes. We will investigate this hypothesis by utilizing a unique resource of samples from ovarian cancer patients with rich genomic data, combined with data from unaffected ovarian tissue. We will characterize chromosome-wide XCI patterns and identify genes that undergo and escape XCI first in normal ovarian tissue. We will then identify genes that differentially escape XCI in ovarian tumors compared to normal ovarian tissue, and determine if chromosome-wide XCI patterns in ovarian tumors are associated with clinical factors. The role of XCI is an understudied area in cancer research, and this project represents the most comprehensive characterization of XCI in ovarian tissue to date. We will better understand tumors at these sites and establish the extent to which XCI patterns are variable and clinically relevant, and inform future studies to examine XCI in tumorigenesis and disease outcome. Notably, the ability to determine a patient’s XCI profile may lead to advances in individualized medicine if associations with clinical features and outcomes are established. Furthermore, the integrative XCI methods developed here will have broader utility to examine other female-specific cancers or cancers that exhibit sex differences in incidence, progression, or outcomes.