@article{LitovkinVanEyndeJoniauetal.2015,
  author    = {Litovkin, Kirill and Van Eynde, Aleyde and Joniau, Steven and Lerut, Evelyne and Laenen, Annouschka and Gevaert, Thomas and Gevaert, Olivier and Spahn, Martin and Kneitz, Burkhard and Gramme, Pierre and Helleputte, Thibault and Isebaert, Sofie and Haustermans, Karin and Bollen, Mathieu},
  title     = {DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0130651},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151705},
  pages     = {e0130651},
  year      = {2015},
  abstract  = {Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95\% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95\% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95\% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.},
  language  = {en}
}
@article{SchubertSpahnKneitzetal.2013,
  author    = {Schubert, Maria and Spahn, Martin and Kneitz, Susanne and Scholz, Claus J{\"u}rgen and Joniau, Steven and Stroebel, Philipp and Riedmiller, Hubertus and Kneitz, Burkhard},
  title     = {Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0065064},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96825},
  year      = {2013},
  abstract  = {Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.},
  language  = {en}
}