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DEVELOPMENT OF DNA METHYLATION BIOMARKERS AS AN
EARLY DETECTION TOOL FOR HUMAN LUNG ADENOCARCINOMA
by
Janice Soratorio Galler
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)
December 2008
Copyright 2008 Janice Soratorio Galler
Object Description
| Title | Development of DNA methylation biomarkers as an early detection tool for human lung adenocarcinoma |
| Author | Galler, Janice Soratorio |
| Author email | galler@usc.edu; janicegaller@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-08-29 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-31 |
| Advisor (committee chair) | Laird-Offringa, Ite |
| Advisor (committee member) |
Rice, Judd Yang, Allen Siegmund, Kimberly |
| Abstract | Lung cancer is the leading cause of cancer-related death in the United States. It is estimated that more than 160,000 lung cancer patients will die of the disease in 2008. Early detection is key to improving patient survival; however, current screening strategies have low specificity and/or sensitivity in detecting early lung cancer. Our focus was to study DNA methylation and its role in lung cancer development and progression with the hope of developing molecular markers for the early detection of lung adenocarcinoma (AD; the most common histology of lung cancer). Understanding the timing of DNA methylation changes during the multi-stage process of AD development could provide a panel of biomarkers potentially used to detect the disease at earlier stages. We have developed a panel of 15 loci that have significant differential methylation between AD and adjacent non-tumor lung tissues (AdjNTL) by MethyLight, a quantitative DNA methylation assay. When used in a panel, all 15 loci showed a sensitivity of 92.85% and specificity of 100%. These tumor-specific DNA methylation markers were used to study whether the same methylation signatures are present in Atypical Adenomatous Hyperplasia (AAH, putative precancerous lesion of lung AD). In our analysis of tissues from AD patients with AAH lesions, we observed variability in the pattern of methylation between the different loci. Some loci (e.g. CDKN2A) were aberrantly methylated even in non-cancerous tissues. Other loci started accumulating methylation marks in AAH (e.g. SFRP1) while other loci do not become hypermethylated until in its invasive state (RASSF1). The difference in timing of methylation between the different loci could be a reflection of the roles of the pathways involved in adeno-carcinogenesis. Additional cancer-specific DNA methylation markers had recently been indentified through high-throughput Illumina GoldenGate Methylation assay.; The onset of DNA methylation of the loci identified by Illumina GoldenGate assay in AD development remains to be elucidated. The knowledge of sequential methylation changes in AAH-AD continuum could yield powerful risk and/or early detection biomarkers for AD. In addition, our findings could provide insights into the natural history of this lethal disease. |
| Keyword | lung cancer; adenocarcinoma; DNA methylation; biomarkers; early detection |
| 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-m1707 |
| Rights | Galler, Janice Soratorio |
| 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-Galler-2419 |
| Archival file | uscthesesreloadpub_Volume44/etd-Galler-2419.pdf |
Description
| Title | Page 1 |
| Full text | DEVELOPMENT OF DNA METHYLATION BIOMARKERS AS AN EARLY DETECTION TOOL FOR HUMAN LUNG ADENOCARCINOMA by Janice Soratorio Galler 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) December 2008 Copyright 2008 Janice Soratorio Galler |
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