Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster C S, Fletcher A, Gerald W L, Moller H, Reuter V, De Bono J S, Scardino P, Cuzick J, Cooper C S
Institute of Cancer Research, Male Urological Cancer Research Centre, Surrey, UK.
Oncogene. 2008 Jan 10;27(3):253-63. doi: 10.1038/sj.onc.1210640. Epub 2007 Jul 16.
New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5' (labelled green) and 3' (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.
由于前列腺癌的自然病程高度可变，因此迫切需要新的前列腺癌管理预测标志物。在诊断时， Gleason评分是评估前列腺癌侵袭性的金标准。然而，最近在前列腺癌中发现TMPRSS2与ERG基因融合，这增加了将ERG基因座的改变用作基于机制的额外预后指标的可能性。荧光原位杂交（FISH）检测用于评估445例接受保守治疗的前列腺癌患者队列中的ERG基因状态。FISH检测发现5'（标记为绿色）和3'（标记为红色）ERG序列分离，这是TMPRSS2-ERG融合的结果，此外还鉴定了21号染色体上串联排列的TMPRSS2和ERG基因序列之间基因组序列的间质缺失。缺乏ERG改变的癌症表现出良好的病因特异性生存率（8年生存率为90%）。我们鉴定出一种新型前列腺癌，其特征是TMPRSS2与ERG序列融合的重复以及ERG 5'端序列的间质缺失（称为“2+Edel”），相比之下，其病因特异性生存率极低（风险比=6.10，95%置信比=3.33-11.15，P<0.001，8年生存率为25%）。在多变量分析中，“2+Edel”除了提供诊断时的Gleason评分和前列腺特异性抗原水平所提供的信息外，还提供了显著的预后信息（P=0.003）。其他个体类型的ERG改变与中等或良好预后相关。我们得出结论，确定ERG基因状态，包括2+Edel中TMPRSS2与ERG序列融合的重复，可将前列腺癌分层为不同的生存类别。
