Genomic profiling reveals distinct pathways of prostate tumorigenesis with clinical implications

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Prostate cancer is clinically heterogeneous ranging from indolent to aggressive metastatic disease. Unfortunately we do not have a reliable way to predict at the time of diagnosis which tumor might be life threatening. We had previously defined three gene-expression subtypes of prostate cancer, one (subtype-1) linked to clinically-indolent behavior, and the others (subtypes-2 and -3) associated with more aggressive disease. By array CGH-based genomic profiling of 64 tumors included in the initial gene expression study, we now discover these subtypes also exhibit distinct spectra of genomic DNA copy number alterations (CNAs). Subtype-1 tumors exhibit characteristic deletions at 5q21 and 6q15, while subtype-2 tumors harbor deletions at 8p21 (NKX3-1) and 21q22 (TMPRSS2-ERG fusion). Therapy-naïve pelvic lymph node metastases, belonging predominantly to subtype-3, display overall higher frequencies of CNA, and in particular gains on 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Other aberrations, like deletions at 12p13 (CDKN1B) and 13q14 (RB1) are frequent but shared among subtypes. Re-examination of expression profiles identifies signatures of androgen-response and of putative ETS target genes in subtypes-1 and -2, respectively. Notably, that aggressive subtypes exhibit significantly lower-frequency deletion at 5q21 and 6q15 implies that aggressive tumors arise largely de novo rather than by progression from indolent cases, with implications for tumor classification and patient management. Our findings reveal distinct genetic pathways of prostate tumorigenesis, and in particular implicate novel tumor suppressor genes at 5q21 and 6q15 within a new framework for investigating the molecular pathogenesis of clinically-indolent prostate cancer.