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BACKGROUND:The practice of personalized medicine has made large strides since the introduction of highthroughput technologies and the vast improvements in computational biotechnology. The personalizedmedicine approach to cancer management holds promise for earlier disease detection, accurate prediction of prognosis, and better treatment options; however, the early experience with personalized medicine has revealed important concerns that need to be addressed before research findings can be translated to the bedside.CONTENT: We discuss several emerging "practical" or "focused" applications of personalized medicine. Molecular testing can have an important positive impact on health and disease management in a number of ways, and the list of specific applications is evolving. This list includes improvements in risk assessment, disease prevention, identification of new diseaserelated mutations, accurate disease classification based on molecular signatures, selection of patients for enrollment in clinical trials, and development of new targeted therapies, especially for metastatic tumors that are refractory to treatment. Several challenges remain to be addressed before genomics information can be applied successfully in the routine clinical management of cancers. Further improvements and investigations are needed in data interpretation, extraction of actionable items, costeffectiveness, how to account for patient heterogeneity and ethnic variation, and how to handle the risk of "incidental findings" in genetic testing.

Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC.

Abstract. Prostate cancer is the leading cancer diagnosed and the second most common cause of cancer related death in the western world. For prognostic monitoring after prostatectomy, recurrent increase of prostate-specific antigen (PSA), the so-called PSA or biochemical relapse remains the leading biomarker. There is currently no biomarker that can accurately predict the risk of relapse at the time of surgery. We analyzed formalin-fixed and paraffin-embedded tissue samples from 52 primary prostate cancers and normal adjacent tissues obtained after radical prostatectomy. Patients were grouped into two categories: i) patients with early biochemical relapse (<1 year after radical prostatectomy) and ii) patients with late or no biochemical relapse (>2 years after surgery). Multiplex real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to identify a miRNA signature that can predict relapse. Results were validated by quantitative RT-PCR analysis. We identified 63 miRNAs that were differentially expressed among the same categories of patients, of whom 35 miRNAs were up-regulated and 28 were down-regulated. Literature search shows that many of these miRNAs have an established prognostic significance in other cancers and can be actively involved in tumor progression. Target prediction analysis showed that predicted targets of these miRNAs could be involved in biological processes and pathways that enhance tumor progression. We experimentally validated the role of one of the dysregulated miRNAs (miR-10b) in relapse using proliferation and wound-healing assay. miRNAs can be reliable predictive markers for biochemical relapse of prostate cancer at the time of radical prostatectomy. This should have significant impact on patient managing plans.

The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.