Identification of prostate cancer-expressed microRNAs associated with clinical recurrence (cR) and prostate cancer-specific survival (PCSS) following radical prostatectomy (RP).

Abstract

21 Background: We previously identified messenger RNAs (mRNAs) whose expression can distinguish aggressive from indolent prostate cancer. Representing multiple key genomic pathways, these mRNAs are significantly associated with cR and PCSS after RP, providing prognostic information beyond PSA, cT stage and Gleason Score. We evaluated microRNA expression in the same specimens for association with cR and PCSS. Methods: All cT1/cT2 prostate cancer pts treated with RP at Cleveland Clinic from 1987-2004 were identified (n~2,600), of which 127 pts w/ cR and 374 pts w/o cR after RP were randomly selected using cohort sampling. RNA was purified from 2 macrodissected FPE tumor specimens per pt. Expression of 76 test and 5 reference microRNAs was quantified by RT-PCR. Cox regression and control of the false discovery rate (FDR) was used to assess reference-normalized microRNA and mRNA expression for association with cR and PCSS. Results: 106 pts with cR and 310 without cR had sufficient RNA and successful microRNA assays. Analysis of primary Gleason pattern tumor tissue for each pt identified 21 microRNAs associated with cR and 13 microRNAs associated with PCSS, with FDR at 10%; 8 microRNAs were associated with both endpoints. Similar analysis of highest Gleason pattern tumor tissue for each pt identified 22 microRNAs associated with cR (17 overlapping with those for the primary Gleason pattern) and 7 microRNAs associated with PCSS, with FDR at 10%; 4 were associated with both endpoints. miR-1, miR-21, miR-93, and miR-106b were associated with both cR and PCSS in primary and highest Gleason pattern specimens. The 76 microRNAs in this study tended to have weaker association with cR and PCSS than the 732 mRNAs. In multivariate analyses, mRNAs and microRNAs provided prognostic information beyond PSA, cT stage, and biopsy Gleason score. MicroRNAs co-express more frequently with each other than with mRNAs, which may indicate distinct biological regulation. Conclusions: Expression of some microRNAs assayed in FPE prostate tumor tissue was associated with cR and PCSS after RP in this study, and may retain prognostic value in the face of tumor heterogeneity.