Sex-Hormones and the TMPRSS2: ERG Fusion in Prostate Cancer Progression

性激素和 TMPRSS2：前列腺癌进展中的 ERG 融合

• 批准号: 8014969
• 负责人: Lorelei Mucci
• 金额: $ 33.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-03 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8014969
• 关键词: 5' Untranslated Regions; Address; Adipose tissue; Adult; Affect; Androgen Receptor; Androgens; Apoptosis; Area; Biological Markers; Body Weight Changes; Body mass index; CYP17A1 gene; CYP19A1 gene; Cancer Prognosis; Castration; Cell Death; Cell Proliferation; Cessation of life; Characteristics; Clinical; Collaborations; Communities; DNA; Data; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; ESR1 gene; ESR2 gene; Estrogens; Event; Exhibits; Family member; Fluorescent in Situ Hybridization; Frequencies; Gene Fusion; Genes; Genetic; Genetic Transcription; Gleason Grade for Prostate Cancer; Gonadal Steroid Hormones; Growth; Health; Health Professional; Heterogeneity; Hormonal; Hormones; Human; Immunohistochemistry; Incidence; Insulin; Lead; Light; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medical Castration; Metabolism; Metastatic Neoplasm to the Bone; Modeling; Molecular; Morbidity - disease rate; Obesity; Oncogenes; Outcome; Pathogenesis; Pathway interactions; Patient Selection; Peptides; Physicians; Plasma; Play; Primary Prevention; Production; Prostate; Prostatic Neoplasms; Proteins; Public Health; Receptor Signaling; Regulation; Research; Research Personnel; Risk; Role; SHBG gene; Secondary Prevention; Signal Transduction; Staging; Stimulus; TMPRSS2 gene; Testosterone; Therapeutic Intervention; Transcript; Tumor Angiogenesis; Tumor Tissue; Tumor stage; United States; Variant; Waist-Hip Ratio; Weight; Western World; adiponectin; base; biobank; cohort; deprivation; follow-up; gene function; hormone regulation; improved; lifestyle factors; men; mortality; novel; outcome forecast; promoter; prospective; repository; response; steroid hormone metabolism; transcription factor; tumor; tumor growth; tumor progression; waist circumference

DESCRIPTION (provided by applicant): We propose to assess the impact of sex-steroid hormones and prostate cancer (PCa) progression in the context of the recently identified TMPRSS2:ERG translocation, a novel gene fusion of the 5'-untranslated region of the androgen-regulated TMPRSS2 promoter and the ETS transcription factor family member. The TMPRSS2:ERG translocation is a common molecular event in PCa, and emerging data (including our own) suggest men with tumors with the translocation tend to have a worse cancer prognosis. The regulation of TMPRSS2 by androgens and possibly estrogens is intriguing and illuminates a potential mechanism whereby sex hormones could drive tumor growth and proliferation leading to worse cancer survival. We have identified 1,500 men diagnosed with incident PCa in the Physicians' Health Study and Health Professionals Follow-up Study during 1982 to 2006, and will continue prospective follow-up through 2012 for outcomes (175 will have developed metastatic or fatal disease). We have assembled a repository of archival tumor tissue, and will characterize the TMPRSS2:ERG tumor status using fluorescent in situ hybridization. We will explore the role of the TMPRSS2:ERG fusion on PCa progression. Moreover, we will examine whether circulating levels of sex hormones or variation in genes involved in sex hormone signaling or metabolism interact with the fusion to affect progression; we hypothesize that men with fusion positive tumors have a worse prognosis if they are exposed to high sex hormone levels. We will evaluate whether obesity, with its known regulation of the hormonal milieu causing higher levels of estrogen and reduced testosterone, is associated with PCa progression by interacting with the TMPRSS2:ERG fusion. At the tumor level, we will examine the relation between fusion status, alone and in concert with hormones, and extent of tumor angiogenesis, cellular proliferation and apoptosis. Finally, we will evaluate whether men with fusion positive tumors have a more favorable response to androgen deprivation therapy compared to those without the TMPRSS2:ERG fusion. Based on the incidence of PCa in the United States and frequency of the fusion, more than 100,000 men diagnosed each year have a fusion positive PCa. If these tumors are indeed more aggressive, this number reflects a considerable burden of men at risk of progression. As such, an understanding of the TMPRSS2:ERG fusion on PCa survival in light of the hormonal milieu could have significant public health impact, and illuminate opportunities for primary and secondary prevention or improved patient selection for specific therapeutic intervention. PUBLIC HEALTH RELEVANCE: PCa is a significant public health burden with respect to morbidity and mortality among men in the Western World. The recent identification of a common novel translocation in PCa, the TMPRSS2:ERG fusion, may help explain the heterogeneity of this disease, although there is still limited research in this area. Our study seeks to explore the role of the TMPRSS2:ERG translocation in PCa progression within two large, community-based cohorts of men with PCa, and to understand whether genetic factors, hormones or lifestyle factors interact with the fusion to impact cancer mortality.

描述(由申请人提供)：我们建议在最近发现的TMPRSS2：ERG易位的背景下评估性类固醇激素与前列腺癌(PCA)进展的影响，ERG易位是雄激素调节的TMPRSS2启动子的5‘-非翻译区和ETS转录因子家族成员的一种新的基因融合。TMPRSS2：ERG易位是前列腺癌中常见的分子事件，新出现的数据(包括我们自己的数据)表明，患有该易位的肿瘤男性往往癌症预后较差。雄激素和可能的雌激素对TMPRSS2的调节是有趣的，并阐明了性激素可能驱动肿瘤生长和增殖导致更差的癌症生存的潜在机制。我们在1982年至2006年的医生健康研究和健康专业人员跟踪研究中确定了1500名被诊断为突发前列腺癌的男性，并将继续前瞻性跟踪到2012年的结果(175人将发展为转移性或致命性疾病)。我们已经建立了一个档案肿瘤组织资料库，并将使用荧光原位杂交来表征TMPRSS2：ERG肿瘤状态。我们将探讨TMPRSS2：ERG融合在PCa进展中的作用。此外，我们将检查循环中的性激素水平或涉及性激素信号或新陈代谢的基因变异是否与融合相互作用，以影响进展；我们假设，患有融合阳性肿瘤的男性如果暴露在高性激素水平下，预后更差。我们将通过与TMPRSS2：ERG融合的相互作用来评估肥胖症是否与前列腺癌进展有关。肥胖症已知调节荷尔蒙环境导致雌激素水平升高和睾酮减少。在肿瘤水平，我们将研究融合状态与肿瘤血管生成、细胞增殖和细胞凋亡的程度之间的关系，包括单独和与激素的协同作用。最后，我们将评估与没有TMPRSS2：ERG融合的男性相比，有融合阳性肿瘤的男性是否对雄激素剥夺治疗有更有利的反应。根据美国PCa的发病率和融合频率，每年有超过10万名被诊断为融合阳性的男性PCa呈阳性。如果这些肿瘤确实更具侵袭性，这个数字反映了有进展风险的男性的相当大的负担。因此，根据激素环境了解TMPRSS2：ERG融合对PCa生存的影响可能会对公共卫生产生重大影响，并阐明一级和二级预防或改善特定治疗干预的患者选择的机会。公共卫生相关性：就西方世界男性的发病率和死亡率而言，前列腺癌是一个重大的公共卫生负担。最近在前列腺癌中发现了一种常见的新易位，TMPRSS2：ERG融合，这可能有助于解释这种疾病的异质性，尽管在这一领域的研究仍然有限。我们的研究旨在探索TMPRSS2：ERG易位在两个大型社区男性前列腺癌队列中的作用，并了解遗传因素、激素或生活方式因素是否与融合相互作用而影响癌症死亡率。