DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer
Abstract/Contents
- Abstract
- Candidate gene based studies have identified a handful of aberrant CpG DNA methylation events in prostate cancer (Brooks et al. 1998; Yegnasubramanian et al. 2004). However, large scale DNA methylation profiles have not been examined for normal prostates or prostate tumors. Additionally, the mechanisms behind these DNA methylation alterations are unknown. In this thesis, I describe the results of my efforts to better understand these previously unexplored areas of biology. For the study presented in this thesis, I quantitatively profiled 95 primary prostate tumors and 86 healthy prostate tissue samples for their DNA methylation levels at 26,333 CpGs representing 14,104 gene promoters by using the Illumina HumanMethylation27 platform. When the profiles of the prostate tissue samples were compared, I observed a substantial number of tumor-specific DNA methylation alterations. A 2-class Significance Analysis of this dataset revealed 5,912 CpG sites with increased DNA methylation and 2,151 CpG sites with decreased DNA methylation in tumors (FDR < 0.8%). Prediction Analysis of this dataset identified 87 CpGs that are the most predictive diagnostic methylation biomarkers of prostate cancer. By integrating available clinical follow-up data, I also identified 69 prognostic DNA methylation alterations that correlate with biochemical recurrence of the tumor. To identify the mechanisms responsible for these genome-wide DNA methylation alterations, I measured the gene expression levels of several DNA methyltransferases (DNMTs) and their interacting proteins by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in tumors. Subsequent transient transfection assays in cultured primary prostate cells revealed that DNMT3B1 and DNMT3B2 overexpression resulted in increased methylation of a substantial subset of CpG sites that also showed tumor-specific increased methylation.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Kobayashi, Yuya |
|---|---|
| Associated with | Stanford University, Department of Genetics |
| Primary advisor | Myers, Richard |
| Primary advisor | Sherlock, Gavin |
| Thesis advisor | Myers, Richard |
| Thesis advisor | Sherlock, Gavin |
| Thesis advisor | Brooks, James |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Thesis advisor | Tang, Hua |
| Advisor | Brooks, James |
| Advisor | Lipsick, Joseph Steven, 1955- |
| Advisor | Tang, Hua |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Yuya Kobayashi. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Yuya Kobayashi
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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