Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention

Prostate cancer (PrCa) is the second most common malignancy in men. More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion. Despite extensive cancer genome/transcriptome data, little is known about the impact of mutations and altered transcription on regulatory networks in the PrCa of individual patients. Using patient-matched normal and tumor samples, we established somatic variations and differential transcriptome profiles of primary ERG-positive prostate cancers. Integration of protein-protein interaction and gene-regulatory network databases defined highly diverse patient-specific network alterations. Different components of a given regulatory pathway were altered by novel and known mutations and/or aberrant gene expression, including deregulated ERG targets, and were validated by using a novel in silico methodology. Consequently, different sets of pathways were altered in each individual PrCa. In a given PrCa, several deregulated pathways share common factors, predicting synergistic effects on cancer progression. Our integrated analysis provides a paradigm to identify druggable key deregulated factors within regulatory networks to guide personalized therapies.前列腺癌（Prostate cancer, PrCa）是男性中第二常见的恶性肿瘤。超过50%的晚期前列腺癌患者存在TMPRSS2-ERG基因融合。尽管目前已积累了大量癌症基因组与转录组数据，但针对单个患者前列腺癌中突变与转录异常对调控网络的影响仍所知有限。本研究借助患者配对的正常组织与肿瘤组织样本，解析了原发性ERG阳性前列腺癌的体细胞变异与差异转录组谱。通过整合蛋白质相互作用与基因调控网络数据库，本研究鉴定出高度多样化的患者特异性网络异常。特定调控通路的不同组分可通过新发突变、已知突变或异常基因表达（包括ERG靶基因的失调）发生改变，并通过新型计算机模拟方法得到验证。因此，每位前列腺癌患者的异常调控通路集合均存在差异。在单例前列腺癌组织中，多条失调通路共享共同调控因子，预示着这些通路对癌症进展存在协同影响。本研究的整合分析为在调控网络中鉴定可靶向的关键失调因子提供了研究范式，可为个性化治疗提供指导。