Lapointe Jacques, Li Chunde, Giacomini Craig P, Salari Keyan, Huang Stephanie, Wang Pei, Ferrari Michelle, Hernandez-Boussard Tina, Brooks James D, Pollack Jonathan R
Department of Pathology, Stanford University, Stanford, California, USA.
Cancer Res. 2007 Sep 15;67(18):8504-10. doi: 10.1158/0008-5472.CAN-07-0673.
Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.
前列腺癌在临床上具有异质性，从惰性疾病到致命疾病不等。基因表达谱分析先前定义了前列腺癌的三种亚型，一种（亚型1）与临床预后良好相关，另外两种（亚型2和亚型3）与更具侵袭性的疾病形式相关。为了在基因组水平上探索疾病异质性，我们对64例前列腺肿瘤标本进行了基于芯片的比较基因组杂交（芯片CGH），其中包括55例原发性肿瘤和9例盆腔淋巴结转移灶。对DNA拷贝数改变（CNA）进行无监督聚类分析，发现了复发性畸变，包括与亚型1基因表达模式相关的6q15缺失组以及肿瘤复发率降低。有监督分析进一步揭示了基因表达亚型之间不同的CNA模式，其中亚型1肿瘤在5q21和6q15处表现出特征性缺失，亚型2病例在8p21（NKX3-1）和21q22处存在缺失（导致TMPRSS2-ERG融合）。淋巴结转移灶主要为亚型3，显示出总体较高的CNA频率，特别是8q24（MYC）和16p13处的增益，以及10q23（PTEN）和16q23处的缺失。我们的研究结果表明，前列腺癌通过有限数量的替代优选遗传途径发展。由此产生的分子遗传亚型为研究前列腺癌生物学提供了一个新框架，并部分解释了该疾病的临床异质性。
