Prostate cancer (PrCa) is the second most common malignancy in men 1 . More than 50% of advanced prostate cancers display the TMPRSS2-ERG fusion 2 . Despite extensive cancer genome/transcriptome 2-4 and phosphoproteome 5 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 6,7 defined highly diverse patient-specific network alterations. We found that different components of a given regulatory pathway were altered by novel and known mutations and/or aberrant gene expression, including deregulated ERG targets, such that 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 key deregulated factors within regulatory networks to guide personalized therapies.The mutational landscapes of primary and advanced/metastatic PrCa have been extensively analyzed 2,3,8,9 , as has been the prevalence of the androgen-sensitive TMPRSS2 promoter fusion with ETS transcription factors 10 , which endows ETS with responsiveness to the androgen receptor (AR) that is frequently overexpressed in antiandrogen-resistant PrCa 11 . Recurrent mutations have been found in genes coding for factors regulating a plethora of pathways and key cellular functions, such as the androgen receptor signaling, PI3K/RAS/RAF/WNT pathways, Extended Data Fig. 5: Patient-specific deregulations of the PDGF and EGFR pathway components for the indicated patients (P). a, Merged network of 10 patients used a background in (b) to (l) for PDGF pathway. j, Merged network of 7 patients used as a background in (k) to (o) for EGFR pathway. Frame and color codes are shown below P12. b to i, deregulated and/or mutated components of the PDGF pathway in each patient. k to o deregulated and/or mutated components of EGFR pathway in each patient. Extended Data Fig. 6: Patient-specific deregulations of the PDGF and EGFR pathway components for the indicated patients (P). a, Network display of deregulated and mutated factors of patient P1 in the WNT, Angiogenesis and Cytokine Pathways to reveal connectivities between the different pathways. b, Similar representation of the de-regulated and mutated factors in P2 for the WNT, PDGF and EGFR pathways.

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