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.

项目总结 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。许多 癌症类型表现出性别之间的发病率差异，这些差异只是部分 可由非遗传因素解释，如荷尔蒙差异、致癌物暴露、生活方式和获得 医疗保健。到目前为止，我们对遗传因素--特别是那些在性别上编码的因素--的理解 染色体--性别差异在癌症发病机制中的作用仍不完全。一个 男性和女性之间的根本遗传差异在于X基因的组成和调控。 染色体(ChrX)；相对于雄性体细胞，雌性体细胞有额外的chrX。大多数基因 在一个拷贝的chrX上，雌性通过X染色体失活(XCI)过程在表观遗传上沉默， 导致一个活跃的(ChrXa)和一个不活跃的(ChrXi)染色体X。此外，我们最近发现 XIST--启动XCI的长非编码RNA--可以在男性的一个子集中表达 癌症。因此，我们假设X染色体的体细胞变化可能会扰乱两者的XCI 女性和男性，导致致癌或有害的基因表达变化。在这个项目中，我们将 通过两个目标研究在男性和女性背景下体细胞chrX改变在癌症中的作用。在目标1中，我们 将支撑我们对易位肾细胞癌(TRCC)的研究，这是肾癌的一种亚型，通常由 通过涉及chrX上的TFE3基因的致癌重排。尽管所有其他肾癌都是男性- 主要的是，tRCC在发病率上显示出约2：1的女性偏见，这促使人们假设 女性体内额外的chrX拷贝会使发生致癌TFE3融合的风险增加一倍。这意味着TFE3 雌性的chrxi可以发生重排，这将需要xci的中断和重新激活。 通常被沉默的基因。我们将开发特定于单倍型的生物信息学方法来区分 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 重排对tRCC中每个chrX同系物的影响。我们还将使用以下工具为TFE3融合建模 CRISPR/Cas9探讨TFE3重排的差异转录和功能意义 涉及chrXa和chrXi。在目标2中，我们将扩展我们令人惊讶的观察结果，即一些男性癌症可以 躯体激活XIST表达。我们将确定XIST在男性中的躯体激活程度 与女性XCI中稳定的chrX沉默有关。我们还将确定躯体 男性XIST激活导致选择性遗传易感性，可能代表特定性别的癌症 依赖关系。该项目将利用创新的基因组和功能遗传方法来探索 关于chrX上的体细胞变化如何参与癌症发病机制的基本问题。更广泛地说， 这项工作试图建立一种新的范式，以帮助我们理解驱动性别偏见的遗传因素。 癌症的发生和发展，并确定新的策略，以特定性别的方式靶向肿瘤。