Project description:The clinical management of prostate cancer is challenging and currently relies primarily on staging, histological grading, and tumor size. In this study, we take advantage of the propensity of prostate cancer to be multifocal and categorize aggressiveness of individual prostate cancer foci based on DNA methylation patterns in primary and metastatic tumors.
Project description:A major challenge in the clinical management of prostate cancer is the inability to definitively diagnose indolent versus aggressive cases. Contributing to this challenge is a lack of basic science understanding of the molecular basis behind aggressiveness subtypes in prostate cancer. DNA methylation is the epigenetic addition of a methyl group to the DNA base cytosine and has been found to regulate cell proliferation and environmental adaptation. We hypothesized that DNA methylation changes are a mechanism by which an aggressive cancer attains phenotypes that distinguish it from indolent cases via disruption of regulatory networks. This hypothesis was tested by comparing DNA methylation between benign prostate and both low grade (Gleason score 6) and high grade (Gleason score 8 to 10) groups. Methylome-wide next generation sequencing was performed on formalin-fixed paraffin embedded (FFPE) samples from radical prostatectomy cases using MBD-isolated genome sequencing (MiGS). This technique uses a DNA methylation binding protein (MBD) to purify fragments from a genomic library with a high level of CpG DNA methylation. These fragments were then sequenced via next generation sequencing, the reads were aligned to a reference genome, and then the reads were counted within non-overlapping 50bp windows genome wide. Statistical analysis was then performed on these windowed counts to produce differentially methylated regions (DMRs). MBD-isolated Genome Sequencing (MiGS) for groups of benign prostate (from cystoprostatectomy), low grade prostate cancer (from radical prostatectomy with Gleason Score 6), and high grade prostate cancer (from radical prostatectomy with Gleason Scores 8 to 10) in both European Americans and African Americans
Project description:The transcription factor GATA2 regulates chemotherapy resistance in prostate cancer. We report a novel GATA2 transcriptional program that has implications for chemotherapy resistance disease and aggressiveness in castration resistant prostate cancer.
Project description:DNA methylation alterations are a universal feature of cancer. In prostate cancer, site specific DNA methylation changes have been suggested as driver in disease initial and progression. Here we provide a comprehensive assessment of DNA methylation changes in prostate cancer patient derived xenograft (PDX) models. We delineate patterns of both site specific and global methylation changes and nominate novel candidates for biomarker development. Genome wide DNA methylation profiling of prostate cancer patient derived xenograft and cell line models using Infinium EPIC arrays
Project description:DNA methylation alterations are a universal feature of cancer. In prostate cancer, site specific DNA methylation changes have been suggested as driver in disease initial and progression. Here we provide a comprehensive assessment of DNA methylation changes in prostate cancer patient derived xenograft (PDX) models. We delineate patterns of both site specific and global methylation changes and nominate novel candidates for biomarker development. Genome wide DNA methylation profiling of prostate cancer patient derived xenograft and cell line models using Infinium EPIC arrays
Project description:p-EMT prostate cancer cells with EMT inducing transcription factor Zeb1 knocked down show increased aggressiveness compared to completely epithelial or mesenchymal controls. Treatment of aggressive p-EMT cells with the demethylating agent 5-azacytidine decreases cell aggressiveness which is corrlated with changes in the methylation profile of cancer silencing genes.
Project description:DNA methylation alterations are a universal feature of cancer. In prostate cancer, site specific DNA methylation changes have been suggested as driver in disease initial and progression. Here we provide a comprehensive assessment of DNA methylation changes in prostate cancer patient derived xenograft (PDX) models. We delineate patterns of both site specific and global methylation changes and nominate novel candidates for biomarker development.
