Cell. 2015 Nov 5;163(4):1011-25. doi: 10.1016/j.cell.2015.10.025.
There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.
原发性前列腺癌之间存在显著的异质性，这在分子异常谱及其多变的临床病程中很明显。作为癌症基因组图谱（TCGA）项目的一部分，我们对333例原发性前列腺癌进行了全面的分子分析。我们的结果揭示了一种分子分类法，其中74%的这些肿瘤属于由特定基因融合（ERG、ETV1/4和FLI1）或突变（SPOP、FOXA1和IDH1）定义的七种亚型之一。表观遗传图谱显示出显著的异质性，包括具有甲基化表型的IDH1突变亚组。雄激素受体（AR）活性广泛且以亚型特异性方式变化，SPOP和FOXA1突变肿瘤的AR诱导转录本水平最高。25%的前列腺癌在PI3K或MAPK信号通路中存在可能可靶向治疗的病变，19%的DNA修复基因失活。我们的分析揭示了原发性前列腺癌之间的分子异质性以及潜在的可靶向治疗的分子缺陷。
