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DNA HYPERMETHYLATION: ITS ROLE IN COLORECTAL TUMORIGENESIS
AND POTENTIAL CLINICAL APPLICATIONS
by
Toshinori Hinoue
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
May 2009
Copyright 2009 Toshinori Hinoue
Object Description
| Title | DNA hypermethylation: its role in colorectal tumorigenesis and potential clinical applications |
| Author | Hinoue, Toshinori |
| Author email | thinoue@usc.edu; tnori22@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2009-03-27 |
| Date submitted | 2009 |
| Restricted until | Restricted until 13 May. 2011. |
| Date published | 2011-05-13 |
| Advisor (committee chair) | Laird, Peter W. |
| Advisor (committee member) |
Coetzee, Gerhard A. Dubeau, Louis Rice, Judd C. |
| Abstract | Aberrant DNA hypermethylation of CpG islands is a common and early event in colorectal tumorigenesis. Promoter DNA hypermethylation is associated with transcriptional gene silencing, and can contribute to tumorigenesis when it occurs at a critical tumor suppressor gene. A distinct subset of colorectal cancers display the CpG island methylator phenotype (CIMP), characterized by an exceptionally high frequency of cancer-specific DNA hypermethylation. Recent studies have shown that an activating mutation of BRAF (BRAFV600E) is specifically associated with CIMP. We used colorectal cancer cell lines and primary tumors to elucidate the molecular mechanisms for the association. We first examined whether expression of BRAFV600E causes CIMP-specific DNA hypermethylation in the CIMP-negative, BRAF wild-type COLO 320DM colorectal cancer cell line. We found that stable expression of BRAFV600E is not sufficient to induce CIMP in our system. Secondly, considering the alternative possibility, we searched for genes whose DNA hypermethylation was tightly linked to BRAFV600E and CIMP in colorectal cancer. Intriguingly, we identified CIMP-dependent DNA hypermethylation and transcriptional inactivation of IGFBP7, a mediator of BRAFV600E-induced cellular senescence and apoptosis. Inactivation of IGFBP7 by DNA hypermethylation may accommodate BRAFV600E by blocking the senescence pathway. Therefore, our work provides a mechanistic rationale for the association between BRAFV600E and CIMP. Moreover, in an attempt to further characterize CIMP-associated DNA hypermethylation, we have quantitatively determined DNA methylation status of 27,578 CpG sites located in 14,495 gene promoters in 100 colorectal tumors and 8 normal mucosae. Through stringent statistical methods, we have identified cancer-specific DNA hypermethylation of 1,036 genes, of which 601 show CIMP-specific DNA hypermethylation. We have also generated gene expression data.; Our most comprehensive list of CIMP targets and their expression data will help us understand the role of CIMP-associated DNA hypermethylation in colorectal tumorigenesis, and provide the opportunity to study structural and sequence characteristics of affected CpG islands. The latter might ultimately give us insights into the underlying basis of CIMP-associated DNA hypermethylation. Finally, we have developed a panel of novel cancer-specific DNA methylation markers, which would potentially be useful for early diagnosis of colorectal cancer using a noninvasive stool DNA test or a minimally invasive blood-based assay. |
| Keyword | colorectal cancer; DNA methylation; CIMP |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2247 |
| Rights | Hinoue, Toshinori |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Hinoue-2850 |
| Archival file | uscthesesreloadpub_Volume32/etd-Hinoue-2850.pdf |
Description
| Title | Page 1 |
| Full text | DNA HYPERMETHYLATION: ITS ROLE IN COLORECTAL TUMORIGENESIS AND POTENTIAL CLINICAL APPLICATIONS by Toshinori Hinoue A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) May 2009 Copyright 2009 Toshinori Hinoue |
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