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

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和前列腺癌（PCa）进展的影响，TMPRSS2:ERG易位是雄激素调节的TMPRSS2启动子和ETS转录因子家族成员的5'-未翻译区域的新基因融合。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，患有这种易位的男性肿瘤往往有较差的癌症预后。雄激素和可能的雌激素对TMPRSS2的调控是有趣的，并阐明了性激素驱动肿瘤生长和增殖导致癌症生存恶化的潜在机制。我们在1982年至2006年的医师健康研究和卫生专业人员随访研究中确定了1500名诊断为偶发PCa的男性，并将继续进行前瞻性随访至2012年的结果（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，并将利用荧光原位杂交表征TMPRSS2:ERG肿瘤状态。我们将探讨TMPRSS2:ERG融合在前列腺癌进展中的作用。此外，我们将研究循环性激素水平或参与性激素信号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，如果男性融合阳性肿瘤暴露于高性激素水平，他们的预后会更差。我们将评估肥胖是否通过与TMPRSS2:ERG融合相互作用与PCa进展有关，肥胖对激素环境的调节导致雌激素水平升高和睾酮水平降低。在肿瘤水平上，我们将研究融合状态（单独或与激素结合）与肿瘤血管生成、细胞增殖和凋亡程度之间的关系。最后，我们将评估融合阳性肿瘤的男性是否比没有TMPRSS2:ERG融合的男性对雄激素剥夺治疗有更有利的反应。根据美国PCa的发病率和融合的频率，每年有超过10万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有进展风险的男性的相当大的负担。因此，了解激素环境下TMPRSS2:ERG融合对前列腺癌生存的影响可能具有重大的公共卫生影响，并为一级和二级预防提供机会，或改善患者对特定治疗干预的选择。公共卫生相关性：前列腺癌是西方世界男性发病率和死亡率方面的重大公共卫生负担。最近在前列腺癌中发现了一种常见的新易位，TMPRSS2:ERG融合，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。我们的研究旨在探讨TMPRSS2:ERG易位在两个大型社区前列腺癌男性队列中前列腺癌进展中的作用，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，从而影响癌症死亡率。

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.