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Genome abnormalities precede prostate cancer and predict clinical relapse.

ABSTRACT: The prediction of prostate cancer clinical outcome remains a major challenge after the diagnosis, even with improved early detection by prostate-specific antigen (PSA) monitoring. To evaluate whether copy number variation (CNV) of the genomes in prostate cancer tumor, in benign prostate tissues adjacent to the tumor (AT), and in the blood of patients with prostate cancer predicts biochemical (PSA) relapse and the kinetics of relapse, 241 samples (104 tumor, 49 matched AT, 85 matched blood, and 3 cell lines) were analyzed using Affymetrix SNP 6.0 chips. By using gene-specific CNV from tumor, the genome model correctly predicted 73% (receiver operating characteristic P = 0.003) cases for relapse and 75% (P < 0.001) cases for short PSA doubling time (PSADT, <4 months). The gene-specific CNV model from AT correctly predicted 67% (P = 0.041) cases for relapse and 77% (P = 0.015) cases for short PSADT. By using median-sized CNV from blood, the genome model correctly predicted 81% (P < 0.001) cases for relapse and 69% (P = 0.001) cases for short PSADT. By using median-sized CNV from tumor, the genome model correctly predicted 75% (P < 0.001) cases for relapse and 80% (P < 0.001) cases for short PSADT. For the first time, our analysis indicates that genomic abnormalities in either benign or malignant tissues are predictive of the clinical outcome of a malignancy.

SUBMITTER: Yu YP

PROVIDER: S-EPMC3385611 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Genome abnormalities precede prostate cancer and predict clinical relapse.

Yu Yan P YP Song Chi C Tseng George G Ren Bao Guo BG LaFramboise William W Michalopoulos George G Nelson Joel J Luo Jian-Hua JH

The American journal of pathology 20120507 6

The prediction of prostate cancer clinical outcome remains a major challenge after the diagnosis, even with improved early detection by prostate-specific antigen (PSA) monitoring. To evaluate whether copy number variation (CNV) of the genomes in prostate cancer tumor, in benign prostate tissues adjacent to the tumor (AT), and in the blood of patients with prostate cancer predicts biochemical (PSA) relapse and the kinetics of relapse, 241 samples (104 tumor, 49 matched AT, 85 matched blood, and 3 ...[more]

PMID: 22569189

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Project description:BackgroundQuantitative high-throughput data deposited in consortia such as International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) present opportunities and challenges for computational analyses.MethodsWe present a computational strategy to systematically rank and investigate a large number (210-220) of clinically testable gene sets, using combinatorial gene subset generation and disease-free survival (DFS) analyses. This approach integrates protein-protein interaction networks, gene expression, DNA methylation, and copy number data, in association with DFS profiles from patient clinical records.ResultsAs a case study, we applied this pipeline to systematically analyze the role of ALDH1A2 in prostate cancer (PCa). We have previously found this gene to have multiple roles in disease and homeostasis, and here we investigate the role of the associated ALDH1A2 gene/protein networks in PCa, using our methodology in combination with PCa patient clinical profiles from ICGC and TCGA databases. Relationships between gene signatures and relapse were analyzed using Kaplan-Meier (KM) log-rank analysis and multivariable Cox regression. Relative expression versus pooled mean from diploid population was used for z-statistics calculation. Gene/protein interaction network analyses generated 11 core genes associated with ALDH1A2; combinatorial ranking of the power set of these core genes identified two gene sets (out of 211 - 1 = 2,047 combinations) with significant correlation with disease relapse (KM log rank p < 0.05). For the more significant of these two sets, referred to as the optimal gene set (OGS), patients have median survival 62.7 months with OGS alterations compared to >150 months without OGS alterations (p = 0.0248, hazard ratio = 2.213, 95% confidence interval = 1.1-4.098). Two genes comprising OGS (CYP26A1 and RDH10) are strongly associated with ALDH1A2 in the retinoic acid (RA) pathways, suggesting a major role of RA signaling in early PCa progression. Our pipeline complements human expertise in the search for prognostic biomarkers in large-scale datasets.

Project description:In 129 Sv autosomal Alport mice, the strial capillary basement membranes (SCBMs) progressively thicken between 5 and 9 weeks of age resulting in a hypoxic microenvironment with metabolic stress and induction of pro-inflammatory cytokines and chemokines. These events occur concomitant with a drop in endocochlear potential and a susceptibility to noise-induced hearing loss under conditions that do not permanently affect age/strain-matched littermates. Here we aimed to gain an understanding of events that occur before the onset of SCBM thickening. Alport stria has normal thickness and shows levels of extracellular matrix (ECM) molecules in the SCBMs commensurate with wild-type mice. Hearing thresholds in the 3-week Alport mice do not differ from those of wild-type mice. We performed RNAseq analysis using RNA from stria vascularis isolated from 3-week Alport mice and wild type littermates. Data was processed using Ingenuity Pathway Analysis software and further distilled using manual procedures. RNAseq analysis revealed significant dysregulation of genes involved in cell adhesion, cell migration, formation of protrusions, and both actin and tubulin cytoskeletal dynamics. Overall, the data suggested changes in the cellular architecture of the stria might be apparent. To test this notion, we performed dual immunofluorescence analysis on whole mounts of the stria vascularis from these same animals stained with anti-isolectin gs-ib4 (endothelial cell marker) and anti-desmin (pericyte marker) antibodies. The results showed evidence of pericyte detachment and migration as well as the formation of membrane ruffling on pericytes in z-stacked confocal images from Alport mice compared to wild type littermates. This was confirmed by TEM analysis. Earlier work from our lab showed that endothelin A receptor blockade prevents SCBM thickening and ECM accumulation in the SCBMs. Treating cultured pericytes with endothelin-1 induced actin cytoskeletal rearrangement, increasing the ratio of filamentous to globular actin. Collectively, these findings suggest that the change in type IV collagen composition in the Alport SCBMs results in cellular insult to the pericyte compartment, activating detachment and altered cytoskeletal dynamics. These events precede SCBM thickening and hearing loss in Alport mice, and thus constitute the earliest event so far recognized in Alport strial pathology.

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Genome abnormalities precede prostate cancer and predict clinical relapse.

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Genome abnormalities precede prostate cancer and predict clinical relapse.

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