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Integrative Genetic and Epigenetic Studies to Identify Prostate Cancer Genes at Chromosomal 8p

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abstract
The Chromosome 8p21.3 (~1.4 Mb) and 8p23.1 (~3.1 Mb) regions were consistently shown to harbor prostate cancer (PCa) genes by both linkage and somatic studies. Additionally, a 0.3 Mb region on 8p21 was recurrently homozygously deleted in prostate tumors. We aimed to evaluate possible PCa susceptibility genes in these three regions with combined genetic and/or epigenetic methods. Following the pilot global methylation study, we found three candidate genes with promoter hypermethylation within these three regions. Bisulfite sequencing verified TNFRSF10C promoter was differentially methylated in 46 out of 59 (78%) tumor samples compared to paired normal samples. And this gene was hemizygously deleted in 44 out of 59 (74.5%) tumors. Methylation and/or deletion of TNFRSF10C gene was correlated with significant decreased mRNA expression of gene in clinical specimens as well (P < 0.001 for tumors harboring both methylation and deletion and P = 0.03 for tumors with only methylation compared with normal samples). Also as part of this project we evaluated other candidate genes close to the three regions on 8p from pilot study. LPL promoter was firstly found methylated in cancer samples, with 21 out of 56 (38%) PCa tumors methylated. Additionally, the preoperative PSA levels were significantly higher in subjects with LPL promoter methylation (p = 0.0012). For the highly proposed PCa susceptibility gene, PPP2R2A, within the recurrent homozygous deletion region, we did comprehensive germline and somatic analyses, including germline mutation screen in 96 probands of hereditary prostate cancer families, 10 common SNPs association analyses in sporadic PCa cases and controls, somatic copy number change analyses and promoter methylation test. It was only found that PPP2R2A was commonly (67.1%) deleted in 141 tumor samples including a homozygous deletion in 3 tumors (2.1%) with no other significant germline or methylation changes. The primary objective of this project was to evaluate PCa susceptibility genes within the three consensus regions on 8p. Until now, we have identified up to 3 genes that contribute to the formation of PCa by different combination of genetic and/or epigenetic modifications.
subject
CGI
chromosomal 8p
deletion
methylation
promoter
prostate cancer
contributor
Cheng, Yu (author)
Xu, Jianfeng (committee chair)
Hawkins, Gregory A. (committee member)
Zheng, Siqun L. (committee member)
Bowden, Donald W. (committee member)
Meyers, Deborah A. (committee member)
date
2011-07-14T20:36:28Z (accessioned)
2012-01-14T09:30:13Z (available)
2011 (issued)
degree
Molecular Genetics & Genomics (discipline)
embargo
2012-01-14 (terms)
identifier
http://hdl.handle.net/10339/33498 (uri)
language
en (iso)
publisher
Wake Forest University
title
Integrative Genetic and Epigenetic Studies to Identify Prostate Cancer Genes at Chromosomal 8p
type
Dissertation

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