Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations inTP53,FLT4,EYA1,NCOR2,CSMD3, andPCDH15are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such asEYA1,CSMD3,FLT4,NCOR2, andPCDH15and found that mutations inEYA1andCSMD3are associated with a poor outcome in prostate cancer.
前列腺癌是一种高度异质性疾病，其死亡率主要归因于转移，但转移的初始步骤尚未得到充分阐明。我们对43例临床试验入组患者的原发性前列腺癌病灶及对应淋巴结转移灶进行了整合性全外显子组测序与转录组分析。研究结果显示，尽管存在部分克隆独立的原发肿瘤病灶，但87%的原发肿瘤病灶与转移灶均起源于共同祖先。我们证实，与白人患者相比，淋巴结转移灶及非裔美国患者中氧化磷酸化相关基因表达上调。进一步研究发现，TP53、FLT4、EYA1、NCOR2、CSMD3及PCDH15基因突变在前列腺癌转移灶中显著富集。这些发现在包含3929例原发肿瘤和2721例转移灶的荟萃分析中得到验证，揭示了转移性前列腺癌病理学的分子改变模式。研究表明淋巴结转移灶包含多个亚克隆，这些亚克隆已存在于原发肿瘤病灶中。我们观察到多个基因突变富集现象，包括EYA1、CSMD3、FLT4、NCOR2和PCDH15等研究不足的基因，并发现EYA1和CSMD3基因突变与前列腺癌不良预后相关。
肿瘤(癌症)患者之家