人磷酸二酯酶4D7（PDE4D7）的表达在TMPRSS2-ERG阳性原发性前列腺癌中升高，并且独立地降低了术后疾病进展的风险。

Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression.

作者信息

Böttcher R, Henderson D J P, Dulla K, van Strijp D, Waanders L F, Tevz G, Lehman M L, Merkle D, van Leenders G J L H, Baillie G S, Jenster G, Houslay M D, Hoffmann R

机构信息

Department of Urology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.

Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow G12 8TA, Scotland.

出版信息

Br J Cancer. 2015 Nov 17;113(10):1502-11. doi: 10.1038/bjc.2015.335.

BACKGROUND

There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples.

METHODS

About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold>3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample.

RESULTS

We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC).

CONCLUSIONS

We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression.

背景

迫切需要发现能够反映分子病理学特征、支撑前列腺癌进展及患者不良预后的生物标志物。我们之前已证明，在前列腺癌细胞系中，PDE4D7在该疾病的晚期病例中表达下调。为进一步研究PDE4D7表达在前列腺癌进展过程中的预后价值，并评估该磷酸二酯酶亚型的下调如何影响疾病转归，我们检测了生理相关的原发性人样本中PDE4D7的表达。

方法

在8个公开的qPCR、Affymetrix外显子1.0 ST芯片和RNA测序数据集中，对约1405份患者样本进行PDE4D7表达筛选。通过将外显子芯片和RNA测序表达数据转换为稳健的z分数，然后应用阈值>3来定义肿瘤样本中的阳性TMPRSS2-ERG基因融合事件，从而确定患者样本的TMPRSS2-ERG基因重排状态。

结果

我们证明PDE4D7表达与原发性肿瘤的发生呈正相关。我们还发现它与TMPRSS2和ETS转录因子家族成员ERG之间高度前列腺癌特异性的基因重排呈正相关。此外，我们发现，在原发性TMPRSS2-ERG阳性肿瘤中，PDE4D7表达与低级别疾病以及初次治疗后进展可能性降低显著正相关。相反，在去势抵抗性前列腺癌（CRPC）中，PDE4D7转录水平显著降低。