Rizzi Federica, Belloni Lucia, Crafa Pellegrino, Lazzaretti Mirca, Remondini Daniel, Ferretti Stefania, Cortellini Piero, Corti Arnaldo, Bettuzzi Saverio
Department of Medicina Sperimentale, University of Parma, Parma, Italy.
PLoS One. 2008;3(10):e3617. doi: 10.1371/journal.pone.0003617. Epub 2008 Oct 31.
Prostate cancer (CaP) is one of the most relevant causes of cancer death in Western Countries. Although detection of CaP at early curable stage is highly desirable, actual screening methods present limitations and new molecular approaches are needed. Gene expression analysis increases our knowledge about the biology of CaP and may render novel molecular tools, but the identification of accurate biomarkers for reliable molecular diagnosis is a real challenge. We describe here the diagnostic power of a novel 8-genes signature: ornithine decarboxylase (ODC), ornithine decarboxylase antizyme (OAZ), adenosylmethionine decarboxylase (AdoMetDC), spermidine/spermine N(1)-acetyltransferase (SSAT), histone H3 (H3), growth arrest specific gene (GAS1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and Clusterin (CLU) in tumour detection/classification of human CaP.
METHODOLOGY/PRINCIPAL FINDINGS: The 8-gene signature was detected by retrotranscription real-time quantitative PCR (RT-qPCR) in frozen prostate surgical specimens obtained from 41 patients diagnosed with CaP and recommended to undergo radical prostatectomy (RP). No therapy was given to patients at any time before RP. The bio-bank used for the study consisted of 66 specimens: 44 were benign-CaP paired from the same patient. Thirty-five were classified as benign and 31 as CaP after final pathological examination. Only molecular data were used for classification of specimens. The Nearest Neighbour (NN) classifier was used in order to discriminate CaP from benign tissue. Validation of final results was obtained with 10-fold cross-validation procedure. CaP versus benign specimens were discriminated with (80+/-5)% accuracy, (81+/-6)% sensitivity and (78+/-7)% specificity. The method also correctly classified 71% of patients with Gleason score<7 versus > or =7, an important predictor of final outcome.
CONCLUSIONS/SIGNIFICANCE: The method showed high sensitivity in a collection of specimens in which a significant portion of the total (13/31, equal to 42%) was considered CaP on the basis of having less than 15% of cancer cells. This result supports the notion of the "cancer field effect", in which transformed cells extend beyond morphologically evident tumour. The molecular diagnosis method here described is objective and less subjected to human error. Although further confirmations are needed, this method poses the potential to enhance conventional diagnosis.
前列腺癌（CaP）是西方国家癌症死亡的主要相关原因之一。尽管在早期可治愈阶段检测到CaP非常理想，但目前的筛查方法存在局限性，需要新的分子方法。基因表达分析增加了我们对CaP生物学的了解，并可能提供新的分子工具，但识别准确的生物标志物以进行可靠的分子诊断是一项真正的挑战。我们在此描述一种新型的8基因标志物：鸟氨酸脱羧酶（ODC）、鸟氨酸脱羧酶抗酶（OAZ）、腺苷甲硫氨酸脱羧酶（AdoMetDC）、亚精胺/精胺N（1）-乙酰转移酶（SSAT）、组蛋白H3（H3）、生长停滞特异性基因（GAS1）、甘油醛-3-磷酸脱氢酶（GAPDH）和聚集素（CLU）在人类CaP肿瘤检测/分类中的诊断能力。
方法/主要发现：通过逆转录实时定量PCR（RT-qPCR）在从41例被诊断为CaP并建议接受根治性前列腺切除术（RP）的患者获得的冷冻前列腺手术标本中检测8基因标志物。在RP之前，患者在任何时候都未接受治疗。用于该研究的生物样本库由66个标本组成：44个是来自同一患者的良性-CaP配对样本。最终病理检查后，35个被分类为良性，31个被分类为CaP。仅使用分子数据对标本进行分类。使用最近邻（NN）分类器以区分CaP和良性组织。通过10倍交叉验证程序获得最终结果的验证。CaP与良性标本的区分准确率为（80±5）%，灵敏度为（81±6）%，特异性为（78±7）%。该方法还正确分类了71% Gleason评分<7与≥7的患者，Gleason评分是最终结果的重要预测指标。
结论/意义：该方法在一组标本中显示出高灵敏度，其中基于癌细胞少于15%，总标本的很大一部分（13/31，等于42%）被认为是CaP。这一结果支持了“癌场效应”的概念，即转化细胞超出形态学上明显的肿瘤范围。这里描述的分子诊断方法是客观的，且较少受人为误差影响。尽管需要进一步确认，但该方法具有增强传统诊断的潜力。
