Setlur Sunita R, Mertz Kirsten D, Hoshida Yujin, Demichelis Francesca, Lupien Mathieu, Perner Sven, Sboner Andrea, Pawitan Yudi, Andrén Ove, Johnson Laura A, Tang Jeff, Adami Hans-Olov, Calza Stefano, Chinnaiyan Arul M, Rhodes Daniel, Tomlins Scott, Fall Katja, Mucci Lorelei A, Kantoff Philip W, Stampfer Meir J, Andersson Swen-Olof, Varenhorst Eberhard, Johansson Jan-Erik, Brown Myles, Golub Todd R, Rubin Mark A
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
J Natl Cancer Inst. 2008 Jun 4;100(11):815-25. doi: 10.1093/jnci/djn150. Epub 2008 May 27.
The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion.
We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided.
We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold).
TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
大多数前列腺癌存在雄激素调节的跨膜蛋白酶丝氨酸2（TMPRSS2）启动子的5'非翻译区与成红细胞转化特异性转录因子家族成员的基因融合。TMPRESS2与v-ets成红细胞增多症病毒E26癌基因同源物（禽类）（ERG）之间的常见融合与更具侵袭性的临床表型相关，这意味着存在由这种融合定义的前列腺癌独特亚类。
我们使用互补DNA介导的退火、选择、连接和延伸来确定瑞典观察等待队列（1987 - 1999年）中455例前列腺癌患者以及美国医师健康研究队列（1983 - 2003年）存档活检样本中6144个转录信息基因的表达谱。使用划分和分类模型确定TMPRSS2 - ERG融合前列腺癌的基因表达特征，并用于计算功能分析。分别通过活力测定和定量聚合酶链反应评估用载体或雌激素化合物处理后雄激素受体阴性（NCI - H660）前列腺癌细胞中的细胞增殖和TMPRSS2 - ERG表达。所有统计检验均为双侧检验。
我们鉴定出一个87基因的表达特征，可将TMPRSS2 - ERG融合前列腺癌作为一个离散的分子实体区分出来（曲线下面积 = 0.80，95%置信区间[CI] = 0.792至0.81；P <.001）。计算分析表明该融合特征与雌激素受体（ER）信号传导相关。用雌激素（活力相对于第0天进行归一化，第8天雌激素与载体相比，平均值 = 2.04对3.40，差异 = 1.36，95%CI = 1.12至1.62）或ERβ激动剂（第8天ERβ激动剂与载体相比，平均值 = 1.86对3.40，差异 = 1.54，95%CI = 1.39至1.69）处理后，NCI - H660细胞的活力降低，但用ERα激动剂处理后活力增加（第8天ERα激动剂与载体相比，平均值 = 4.36对3.40，差异 = 0.96，95%CI = 0.68至1.23）。同样，用ERβ激动剂处理后TMPRSS2 - ERG的表达降低（相对于内部对照的倍数变化，第24小时ERβ激动剂与载体相比，NCI - H660，平均值 = 0.57对1.0倍，差异 = 0.43倍，95%CI = 0.29至0.57倍），而用ERα激动剂处理后表达增加（第24小时ERα激动剂与载体相比，平均值 = 5.63对1.0倍，差异 = 4.63倍，95%CI = 4.34至4.92倍）。
TMPRSS2 - ERG融合前列腺癌是一个独特的分子亚类。TMPRSS2 - ERG表达受一种新的ER依赖性机制调节。
