Towards Understanding Prostate Cancer Heterogeneity

描述（由申请人提供）：前列腺癌（PCA）是一种常见的临床异质性疾病，其进展具有显著的可变性。本提案的重点是描述我们小组发现的PCA中的一种新的易位，并检查易位在疾病进展中的作用。通过应用新的生物信息学方法，我们的研究小组确定了PCA中常见的易位，涉及雄激素密切调节基因TMPRSS2 （21q22.3）和ETS转录因子家族成员ERG （21q22.2）或ETV1 （7p21.2）。这种易位在侵袭性前列腺癌和20%的高级别前列腺上皮内瘤变（PIN）中发现。TMPSS2-ERG前列腺癌与较高的肿瘤分期和前列腺癌特异性死亡相关。TMPRSS2是雄激素调控程度最高的基因之一。自我们最初的报告以来，我们进一步发现大约60%的TMPRSS2- ets易位的肿瘤在21号染色体上有缺失，涉及TMPRSS2和ERG之间的区域。易位相关缺失的存在，如在CML中所见，可能为PCA的临床和遗传异质性提供重要的见解。因此，我们的总体假设是TMPRSS2-ETS家族癌基因融合蛋白驱动PCA分子多样性和临床进展。我们建议通过追求以下具体目标来验证这一假设：在目标1中，我们将描述PCA中与TMPRSS2-ETS易位相关的缺失频率和程度。在目标2中，我们将确定与独特的TMPRSS2-ETS家族易位和缺失相关的关键基因组改变。在Aim 3中，我们将开发原位试验来评估融合状态作为PCA特异性死亡或转移性疾病发展的预测因子。在本文的结论中，我们将在大范围的PCA样本（n= 150）和基于人群的队列（n=1275）中表征TMPRSS2-ETS易位和缺失的频率。我们将开发优化的FISH检测方法对pca进行亚分类，并确定与易位/缺失状态相关的二次分子改变。最后，我们将确定FISH测定（或其他原位测试）是否可以用作预后生物标志物。

DESCRIPTION (provided by applicant): Prostate cancer (PCA) is a common and clinically heterogeneous disease with marked variability in progression. This proposal focuses on characterizing a novel translocation in PCA identified by our group, and examining the role of the translocation in disease progression. By applying a new bioinformatics approach, our group identified a common translocation in PCA, involving the tightly androgen regulated gene TMPRSS2 (21q22.3) and ETS transcription factor family members, either ERG (21q22.2) or ETV1 (7p21.2). This translocation is detected in invasive PCA and in 20% of high-grade prostatic intraepithelial neoplasia (PIN). TMPSS2-ERG PCA are associated with higher tumor stage and PCA specific death. TMPRSS2 is one of the most highly androgen regulated genes. Since our original report, we have further discovered that approximately 60% of tumors with TMPRSS2-ETS translocations harbor deletions on chromosome 21 involving the region between TMPRSS2 and ERG. The presence of translocation-associated deletions, as seen in CML, may provide important insight into the clinical and genetic heterogeneity of PCA. Therefore, our overarching hypothesis is that the TMPRSS2-ETS family oncogene fusion proteins drive PCA molecular diversity and clinical progression. We propose testing this hypothesis by pursuing the following specific aims: In Aim 1, we will characterize the frequency and extent of deletions associated with the TMPRSS2-ETS translocations in PCA. In Aim 2, we will identify critical genomic alterations associated with the distinct TMPRSS2-ETS family translocations and deletions. In Aim 3, we will develop in situ tests to evaluate fusion status as a predictor of PCA specific death or development of metastatic disease. At the conclusion of this proposal, we will have characterized the frequency of TMPRSS2-ETS translocations and deletions in a wide range of PCA samples (n>150) and a population-based cohort (n=1275). We will develop optimized FISH assays to sub-classify PCAs and identify secondary molecular alterations associated with the translocation/deletion status. Finally, we will determine if FISH assays (or other in situ tests) can be employed as a prognostic biomarker.