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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要癌症是全球主要的公共卫生问题，也是美国第二大死亡原因。许多癌症类型显示性别之间的入射率差异，这些差异仅部分是可以通过非遗传因素来解释，例如激素差异，致癌物暴露，生活方式和进入卫生保健。迄今为止，我们对遗传因素的理解 - 尤其是在性别上编码的因素染色体 - 导致癌症发病机理的性别特异性差异仍然不完整。一个男性和女性之间的基本遗传差异是x-的组成和调节染色体（CHRX）;相对于雄性体细胞，雌性体细胞具有额外的ChRX。大多数基因通过X染色体失活（XCI）的过程，在女性中的ChRX副本上被表观遗传沉默。导致一个活性（CHRXA）和一个无活性（CHRXI）染色体X。此外，我们最近发现了 XIST - 启动XCI的长的非编码RNA - 可以在男性的子集中表达癌症。因此，我们假设X染色体的体细胞改变可能会扰动XCI 女性和男性，导致致癌基因表达变化。在这个项目中，我们将通过两个目标研究男性和女性环境中癌症中体细胞CHRX改变的作用。在AIM 1中，我们将锚定我们在易位肾细胞癌（TRCC）方面的研究，肾癌的亚型通常驱动通过涉及CHRX上TFE3基因的致癌重排。虽然所有其他肾脏癌都是男性 - 主要的TRCC显示出〜2：1的女性偏见，这促使假设存在女性中CHRX的额外副本增加了发展致癌TFE3融合的风险。这意味着TFE3 重排可能是由女性中的Chrxi引起的，这将有必要破坏XCI和重新激活一般沉默的基因。我们将开发单倍型特异性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 TRCC中每个CHRX同源物的重新排列的后果。我们还将使用 CRISPR/CAS9探索TFE3重排的差分转录和功能含义涉及Chrxa vs Chrxi。在AIM 2中，我们将扩大某些男性癌症可以的惊喜观察体面激活Xist表达。我们将确定男性中Xist的体细胞激活的程度是与女性XCI中看到的稳定ChRX沉默的特征有关。我们还将确定是否体细胞男性中的XIST激活承认可能代表性别特异性癌症的选择性遗传脆弱性依赖性。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的体细胞改变如何促进癌症发病机理的基本问题。更广泛地这项工作旨在为我们理解推动性偏见的遗传因素建立新的范式癌症倡议和进步，并以性别特定方式确定针对肿瘤的新型策略。