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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

基本信息

批准号：
8433476
负责人：
Lorelei Mucci
金额：
$ 31.57万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-03 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433476
关键词：
5&apos 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 Markers 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

项目摘要

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.

描述（由申请人提供）：我们建议在最近鉴定的TMPRSS 2：ERG易位的背景下评估性类固醇激素和前列腺癌（PCa）进展的影响，TMPRSS 2：ERG易位是雄激素调节的TMPRSS 2启动子的5 '-非翻译区和ETS转录因子家族成员的新型基因融合。TMPRSS 2：ERG易位是PCa中常见的分子事件，新出现的数据（包括我们自己的数据）表明患有易位肿瘤的男性往往具有更差的癌症预后。雄激素和可能的雌激素对TMPRSS 2的调节是有趣的，并阐明了性激素可以驱动肿瘤生长和增殖从而导致更差的癌症存活率的潜在机制。我们在1982年至2006年的医生健康研究和健康专业人员随访研究中确定了1,500名被诊断为PCa事件的男性，并将继续前瞻性随访至2012年（175人将发展为转移性或致命性疾病）。我们已经组装了一个档案肿瘤组织库，并将使用荧光原位杂交表征TMPRSS 2：ERG肿瘤状态。我们将探索TMPRSS 2：ERG融合对PCa进展的作用。此外，我们将研究性激素的循环水平或参与性激素信号传导或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，如果患有融合阳性肿瘤的男性暴露于高性激素水平，则预后更差。我们将评估肥胖是否与其已知的激素环境调节有关，引起雌激素水平升高和睾酮水平降低，通过与TMPRSS 2：ERG融合相互作用与PCa进展相关。在肿瘤水平，我们将研究融合状态，单独和与激素，肿瘤血管生成，细胞增殖和凋亡的程度之间的关系。最后，我们将评估与没有TMPRSS 2：ERG融合的患者相比，融合阳性肿瘤患者对雄激素剥夺治疗是否有更有利的反应。根据美国PCa的发病率和融合频率，每年有超过100，000名男性被诊断为融合阳性PCa。如果这些肿瘤确实更具侵袭性，那么这个数字反映了处于进展风险中的男性的相当大的负担。因此，根据激素环境对TMPRSS 2：ERG融合对PCa存活的理解可能具有显著的公共卫生影响，并阐明了一级和二级预防或改善患者选择以进行特定治疗干预的机会。