Tomlins Scott A, Alshalalfa Mohammed, Davicioni Elai, Erho Nicholas, Yousefi Kasra, Zhao Shuang, Haddad Zaid, Den Robert B, Dicker Adam P, Trock Bruce J, DeMarzo Angelo M, Ross Ashley E, Schaeffer Edward M, Klein Eric A, Magi-Galluzzi Cristina, Karnes R Jeffrey, Jenkins Robert B, Feng Felix Y
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
GenomeDx Bioscience Inc., Vancouver, British Columbia, Canada.
Eur Urol. 2015 Oct;68(4):555-67. doi: 10.1016/j.eururo.2015.04.033. Epub 2015 May 8.
Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests.
To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping.
DESIGN, SETTING, AND PARTICIPANTS: We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS(+)) or SPINK1 overexpression (SPINK1(+)).
Associations with clinical features and outcomes by multivariate logistic regression analysis and receiver operating curves.
The m-ERG classifier showed 95% accuracy in an independent validation subset (155 samples). Across cohorts, 45% of PCas were classified as m-ERG(+), 9% as m-ETS(+), 8% as m-SPINK1(+), and 38% as triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Gene expression profiling supports three underlying molecularly defined groups: m-ERG(+), m-ETS(+), and m-SPINK1(+)/triple negative. On multivariate analysis, m-ERG(+) tumors were associated with lower preoperative serum prostate-specific antigen and Gleason scores, but greater extraprostatic extension (p<0.001). m-ETS(+) tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1(+)/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different among subtypes.
A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathologic differences were found among subtypes based on global expression patterns.
Molecular subtyping of prostate cancer can be achieved using extra data generated from a clinical-grade, genome-wide expression-profiling prognostic assay (Decipher). Transcriptomic and clinical analysis support three distinct molecular subtypes: (1) m-ERG(+), (2) m-ETS(+), and (3) m-SPINK1(+)/triple negative (m-ERG(-)/m-ETS(-)/m-SPINK1(-)). Incorporation of subtyping into a clinically available assay may facilitate additional applications beyond routine prognosis.
前列腺癌（PCa）分子亚型基本上由相互排斥的事件定义，包括ETS基因融合（最常见的是涉及ERG）和SPINK1过表达。临床评估可能有助于疾病分层，补充现有的预后检测方法。
确定基于微阵列的分子亚型分析的分析有效性和临床病理相关性。
设计、研究地点和参与者：我们分析了来自8个根治性前列腺切除术队列的1577例患者的Affymetrix基因芯片表达谱，其中1351例使用在美国加利福尼亚州圣地亚哥的GenomeDx Biosciences公司进行的Decipher预后检测（该实验室具有临床实验室改进修正案认证）进行评估。基于微阵列（m-）的随机森林ERG分类模型经过训练和验证。使用异常值表达分析来预测其他相互排斥的非ERG ETS基因重排（ETS(+)）或SPINK1过表达（SPINK1(+)）。
通过多变量逻辑回归分析和受试者工作曲线分析与临床特征和结果的相关性。
m-ERG分类器在独立验证子集（155个样本）中显示出95%的准确率。在各个队列中，45%的前列腺癌被分类为m-ERG(+)，9%为m-ETS(+)，8%为m-SPINK1(+)，38%为三阴性（m-ERG(-)/m-ETS(-)/m-SPINK1(-)）。基因表达谱支持三个潜在的分子定义组：m-ERG(+)、m-ETS(+)和m-SPINK1(+)/三阴性。多变量分析显示，m-ERG(+)肿瘤与术前血清前列腺特异性抗原水平较低和Gleason评分较低相关，但前列腺外侵犯更严重（p<0.001）。m-ETS(+)肿瘤与精囊侵犯相关（p=0.01），而m-SPINK1(+)/三阴性肿瘤的Gleason评分较高，在黑人/非裔美国患者中更常见（p<0.001）。各亚型之间的临床结果无显著差异。
一种临床可用的预后检测方法（Decipher）也可以评估前列腺癌分子亚型，无需额外检测。基于整体表达模式发现各亚型之间存在临床病理差异。
前列腺癌分子亚型分型可通过临床级全基因组表达谱预后检测（Decipher）产生的额外数据实现。转录组学和临床分析支持三种不同的分子亚型：（1）m-ERG(+)，（2）m-ETS(+)，和（3）m-SPINK1(+)/三阴性（m-ERG(-)/m-ETS(-)/m-SPINK1(-)）。将亚型分型纳入临床可用检测方法可能有助于在常规预后之外的更多应用。
