Reduced DNA Repair Capacity Leads to Increased Risk of Uterine Fibroids (UFs) in African Americans

DNA 修复能力降低导致非裔美国人患子宫肌瘤 (UF) 的风险增加

• 批准号: 10163705
• 负责人: WINSTON E THOMPSON
• 金额: $ 38.49万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163705
• 关键词: Address; Adult; African American; Animal Model; Attenuated; Benign; Bioinformatics; Caucasians; Cell Compartmentation; Center for Translational Science Activities; ChIP-seq; Cholecalciferol; Chronic; Clinical; Color; Communities; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Development; Discipline; Disease susceptibility; Doxercalciferol; Endocrine Disruptors; Environmental Exposure; Epigenetic Process; Estrogens; Ethnic Origin; Etiology; Evaluation; Exhibits; Exposure to; FDA approved; Face; Fertility; Fibroid Tumor; Frequencies; Functional disorder; Future; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Gold; Growth; Health; Healthcare; Hormonal; Human; Hysterectomy; Investigation; Isoflavones; Knowledge; Laboratories; Leiomyoma; Lesion; Life; Literature; MLH1 gene; Maps; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mutation; Myometrial; National Institute of Environmental Health Sciences; Operative Surgical Procedures; Ovarian; Pathogenesis; Penetrance; Physiological; Polycomb; Predisposition; Prevalence; Proteins; Publications; Quality of life; Race; Rattus; Reporting; Risk; Role; SIRT1 gene; Sampling; Sister; Somatic Mutation; Statistical Data Interpretation; System; TP53 gene; Therapeutic; Tissues; Toxic Environmental Substances; Tumor Suppressor Genes; Uterine Fibroids; Uterus; Woman; Women' s Health; analog; animal data; cost; driver mutation; early life exposure; epigenomics; estrogenic; ethnic disparity; experience; gene repair; genistin; genome-wide; health disparity; high risk; histone methylation; in vivo; individualized medicine; insight; mouse model; myometrium; neonatal exposure; neoplastic; novel; paricalcitol; precision medicine; prenatal exposure; progenitor; response; soy; stem cell biology; stem cell expansion; stem cell population; stem cells; transcriptome sequencing; treatment choice; tumor; vitamin analog; whole genome; xenoestrogen

Abstract Uterine Fibroids (UFs, AKA: leiomyoma) are the most important benign neoplastic threat to women's health. They are the most common cause of hysterectomy causing untold personal consequences and hundreds of billions of health care dollars worldwide. Currently, there is no long term effective FDA-approved medical treatment available, and surgery is the mainstay. The etiology of UFs is not fully understood. In this regard, we and others have recently reported that somatic mutations in the gene encoding the transcriptional Mediator subunit MED12 are found to occur at a high frequency (~85%) in UFs. UFs likely originate when a Med12 mutation occurs in a myometrial stem cell converting it into a tumor-forming stem cell leading to a clonal fibroid lesion. UFs do not affect all races equally. Increased prevalence of UFs in African- American (AA) women has been consistently observed for >120 years. The molecular attributes behind UFs ethnic disparity are not fully realized; however, a growing body of literature implicates unfavorable early life environmental exposures as potentially important contributors. Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in adult life. In the Eker UF rat model, we have recently reported in PNAS that early life exposure to environmental xeno-estrogens increased tumor-suppressor-gene penetrance in adult rats up to ~100%. Compelling preliminary data from our laboratory further identified that such exposure exerts two alterations in exposed rat myometrium: (1) permanently expands myometrial stem cell compartment and, (2) decreases DNA damage repair capacity. Quantitative PrimePCR array indicated that several DNA damage repair genes are significantly down regulated including RAD50, Sirt, and TP53 in myometrium from rats neonatally exposed to xenoestrogens. Importantly, in the human equivalent, we have encountered similar observations. MyoF (high risk myometrium from fibroid uteri) exhibited expanded myometrial stem cell compartment as well as a decrease in DNA damage repair capacity as compared to MyoN (normal myometrium from healthy fibroid-free uteri). This was significantly more noticeable in AA women. Importantly, key DNA repair genes of RAD50, Sirt1, MLH1, and MLH3 were markedly decreased in MyoF vs MyoN. Our central Hypothesis: Early life exposure, during the sensitive period of uterine development, to environmental toxicants, which is more prevalent in AA, permanently expands the number of myometrial stem cells as well as permanently reprograms and attenuates key DNA damage repair genes leading to reduced myometrial DNA damage repair capacity. Chronic reduction in DNA repair capacity eventually leads to the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells and subsequently leads to the development of UFs. We will address this hypothesis using the following three specific aims; Specific Aim 1: Determine whether a small but distinct myometrial stem cell population serves as pre-fibroid tumor progenitors in AA versus Caucasian (C) women. Specific Aim 2: Identify PcG/ TrxG (histone methylation regulators) regulated DNA repair target genes that contribute to developmental reprogramming in UF development. Specific Aim 3: Characterize whether Vitamin D3 is capable of increasing DNA repair capacity via reversing disrupted epigenetic programming in myometrial stem cells. Impact: These paradigm shifting concepts will enable us to identify genomic and epigenomic risk profiles associated with increased susceptibility to UFs in AA women. Such knowledge will inform an efficient precision medicine approach towards the development of novel preventative and therapeutics strategies for this common health disparity challenge.

抽象的 子宫肌瘤（UFS，又名：平滑肌瘤）是对妇女健康的最重要的良性肿瘤威胁。他们是 子宫切除术最常见的原因，导致个人后果和数百亿美元的医疗保健美元 全世界。目前，尚无长期有效的FDA批准的医疗，手术是 支柱。 UFS的病因尚未完全理解。在这方面，我们和其他人最近报告说躯体 发现编码转录介质亚基MED12的基因突变发生在高频（〜85％） 在UFS中。当Med12突变发生在肌层干细胞中时，UF可能起源于肿瘤形成 干细胞导致克隆肌瘤病变。 UFS并不平等影响所有种族。非洲UF的患病率增加 美国（AA）妇女始终被观察到了120年。 UFS种族差异背后的分子属性 没有完全实现；但是，越来越多的文学片段暗示不利的早期生活环境暴露 潜在的重要贡献者。在敏感的开发窗口期间的环境暴露可以重新编程 正常的生理反应并改变了成年后期的疾病敏感性。在Eker UF大鼠模型中，我们最近有 报道PNA中，早期寿命暴露于环境异种雌激素中增加了肿瘤抑制剂 - 基因的渗透率 成年大鼠最多100％。我们实验室的引人入胜的初步数据进一步确定，这种暴露施加了两个 暴露大鼠子宫肌矩阵的改变：（1）永久膨胀心脏体干细胞室，（2）降低 DNA损伤维修能力。定量PrimePCR阵列表明几个DNA损伤修复基因是 显着下调的调节，包括来自新生大鼠的肌层中的Rad50，Sirt和TP53 异雌激素。重要的是，在人类等效方面，我们遇到了类似的观察。 Myof（高风险 肌瘤的子宫肌层表现出膨胀的肌层干细胞室以及DNA的降低 与Myon（健康肌瘤的正常子宫肌矩阵）相比，损伤修复能力。这是显着的 在AA女性中更明显。重要的是，RAD50，SIRT1，MLH1和MLH3的关键DNA修复基因显着 Myof与Myon的减少。我们的中心假设：在子宫敏感时期的早期生活暴露 开发，环境毒物，在AA中更为普遍，永久扩大肌层数量 干细胞以及永久重新编程并减弱关键的DNA损伤修复基因，导致肌层降低 DNA损伤维修能力。 DNA修复能力的慢性降低最终导致突变的出现 例如肌层干细胞中的MED12将其转化为肌瘤形成肿瘤的干细胞，然后导致 UFS的发展。我们将使用以下三个特定目标来解决这一假设。具体目标1：确定 在AA与高加索人的纤维纤维肿瘤前祖细胞中，小但独特的肌层干细胞群是否具有 （c）女性。特定目标2：识别PCG/ TRXG（组蛋白甲基化调节剂）调节的DNA修复靶基因 有助于UF开发中的发展重新编程。特定目标3：表征维生素D3是否为 能够通过逆转肌层干细胞中的表观遗传编程来增加DNA修复能力。影响： 这些范式转移概念将使我们能够识别与增加相关的基因组和表观基因组风险概况 在AA妇女中对UF的敏感性。这些知识将为有效的精确医学方法提供给 针对这种常见的健康差异挑战的新型预防和治疗策略的发展。