Probing the role of somatic X-chromosome alterations in shaping cancer sex differences

探讨体细胞 X 染色体改变在塑造癌症性别差异中的作用

• 批准号: 10780163
• 负责人: Srinivas Raghavan Viswanathan
• 金额: $ 54.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10780163
• 关键词: Automobile Driving; Bioinformatics; CRISPR screen; CRISPR/Cas technology; Carcinogen exposure; Cause of Death; Cells; Chromosomal Stability; Chromosome abnormality; Chromosomes; Dependence; Development; Environmental Risk Factor; Epigenetic Process; Equilibrium; Experimental Models; Female; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Transcription; Genomic approach; Genomics; Haplotypes; Homologous Gene; Hormonal; Incidence; Lead; Life Style; Malignant Neoplasms; Methods; Modeling; Mutation; Oncogenic; Outcome; Pathogenesis; Phenotype; Play; Process; Public Health; Regulation; Renal Cell Carcinoma; Renal carcinoma; Risk; Role; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; Somatic Cell; System; TFE3 gene; Testing; United States; Untranslated RNA; Work; X Chromosome; X Inactivation; autosome; cancer genomics; cancer initiation; cancer type; cohort; genetic approach; genome-wide; genomic data; health care availability; innovation; male; non-genetic; novel strategies; novel therapeutic intervention; sex; tumor; tumor initiation; tumor progression

PROJECT SUMMARY Cancer is a major global public health problem and the second leading cause of death in the United States. Many cancer types display differences in incidence between the sexes, and these differences are only partially explainable by non-genetic factors, such as hormonal differences, carcinogen exposure, lifestyle, and access to health care. To date, our understanding of how genetic factors – particularly those encoded on the sex chromosomes – contribute to sex-specific differences in cancer pathogenesis has remained incomplete. A fundamental genetic difference between males and females is in the composition and regulation of the X- chromosome (chrX); relative to male somatic cells, female somatic cells have an extra chrX. Most of the genes on one copy of chrX in females are epigenetically silenced via the process of X-chromosome inactivation (XCI), resulting in one active (chrXa) and one inactive (chrXi) chromosome X. Additionally, we have recently discovered that XIST – the long non-coding RNA that initiates XCI – can be somatically expressed in a subset of male cancers. We therefore hypothesize that somatic alterations of the X chromosome may perturb XCI in both females and males, leading to either oncogenic or deleterious gene expression changes. In this project, we will study the role of somatic chrX alterations in cancer in both male and female contexts via two aims. In Aim 1, we will anchor our studies in translocation renal cell carcinoma (tRCC), a subtype of kidney cancer usually driven by oncogenic rearrangements involving the TFE3 gene on chrX. While all other kidney cancers are male- predominant, tRCC displays a ~2:1 female bias in incidence, prompting the hypothesis that the presence of an extra copy of chrX in females doubles the risk for developing oncogenic TFE3 fusions. This implies that TFE3 rearrangements can arise from chrXi in females, which would necessitate a disruption of XCI and the reactivation of ordinarily silenced genes. We will develop haplotype-specific bioinformatic methods to distinguish between chrXa and chrXi and deploy these methods across a range of genomic datasets to understand the transcriptional consequences of rearrangements on each of the chrX homologs in tRCC. We will also model TFE3 fusions using CRISPR/Cas9 to explore the differential transcriptional and functional implications of TFE3 rearrangements involving chrXa vs chrXi. In Aim 2, we will expand upon our surprising observation that some male cancers can somatically activate XIST expression. We will determine to what extent somatic activation of XIST in males is associated with the features of stable chrX silencing seen in female XCI. We will also determine whether somatic XIST activation in males confers selective genetic vulnerabilities that may represent sex-specific cancer dependencies. This project will leverage innovative genomic and functional genetic approaches to explore fundamental questions about how somatic alterations on chrX contribute to cancer pathogenesis. More broadly, this work seeks to establish a new paradigm for our understanding of the genetic factors that drive sex bias in cancer initiation and progression and to identify novel strategies to target tumors in a sex-specific fashion.

项目概要 癌症是一个主要的全球公共卫生问题，也是美国第二大死亡原因。 癌症类型在性别之间的发病率存在差异，并且这些差异只是部分差异 可以用非遗传因素来解释，例如荷尔蒙差异、致癌物质暴露、生活方式和获取途径 迄今为止，我们对遗传因素——尤其是那些与性别有关的因素——如何编码的了解。 染色体——导致癌症发病机制中性别特异性差异的因素仍然不完整。 男性和女性之间的根本遗传差异在于X-的组成和调节 染色体（chrX）；相对于雄性体细胞，雌性体细胞多了一个chrX基因。 女性体内的一个 chrX 拷贝通过 X 染色体失活 (XCI) 过程而被表观遗传沉默， 导致一条活性 (chrXa) 和一条非活性 (chrXi) X 染色体。此外，我们最近发现 XIST（启动 XCI 的长非编码 RNA）可以在男性亚群中体细胞表达 因此，我们认为 X 染色体的体细胞改变可能会干扰这两种癌症的 XCI。 女性和男性，导致致癌或有害的基因表达变化。 在目标 1 中，我们通过两个目标研究体细胞 chrX 改变在男性和女性癌症中的作用。 将把我们的研究重点放在易位肾细胞癌（tRCC）上，这是一种通常由肾癌引起的亚型 涉及 chrX 上 TFE3 基因的致癌重排，而所有其他肾癌都是男性。 tRCC 占主导地位，其发病率显示出大约 2:1 的女性偏见，这促使人们假设 tRCC 的存在 女性体内额外的 chrX 拷贝使发生致癌 TFE3 融合的风险增加一倍，这意味着 TFE3 融合。 女性体内的 chrXi 可能会发生重排，这将需要破坏 XCI 并重新激活 我们将开发单倍型特异性的生物信息学方法来区分它们。 chrXa 和 chrXi 并在一系列基因组数据集中部署这些方法以了解转录 tRCC 中每个 chrX 同源物重排的后果我们还将使用 TFE3 融合进行建模。 CRISPR/Cas9 探索 TFE3 重排的差异转录和功能影响 chrXa 与 chrXi 在目标 2 中，我们将扩展我们令人惊讶的观察结果，即某些男性癌症可以 我们将确定男性 XIST 的体细胞激活程度。 与女性 XCI 中观察到的稳定 chrX 沉默的特征相关我们还将确定是否与体细胞相关。 男性中的 XIST 激活赋予选择性遗传脆弱性，可能代表性别特异性癌症 该项目将利用创新的基因组和功能遗传学方法来探索依赖性。 更广泛地说，关于 chrX 的体细胞改变如何促进癌症发病机制的基本问题。 这项工作旨在为我们理解导致性别偏见的遗传因素建立一个新的范式。 癌症的发生和进展，并确定以性别特异性方式靶向肿瘤的新策略。