Aberrant DNA Methylation and Cancer: A Global Analysis of Promoter Hypermethylation in Human Lung Cancers

DSpace/Manakin Repository

Aberrant DNA Methylation and Cancer: A Global Analysis of Promoter Hypermethylation in Human Lung Cancers

Show simple item record


dc.contributor.advisor Minna, John D. en
dc.creator Shames, David S. en
dc.date.accessioned 2010-07-12T17:37:27Z en
dc.date.available 2010-07-12T17:37:27Z en
dc.date.issued 2006-12-20 en
dc.identifier.other en
dc.identifier.uri http://hdl.handle.net/2152.5/334 en
dc.description.abstract Tumor-acquired alterations in DNA methylation include both genome-wide hypomethylation and locus specific hypermethylation. Global loss of DNA methylation destabilizes chromatin architecture, augments genomic instability, and may reactivate repetitive element expression. Promoter hypermethylation often coincides with loss of heterozygosity at the same loci, and together these events can result in loss of function of the gene in tumor cells. The "rules" governing which genes are methylated during the pathogenesis of individual cancers are unknown; however, it is known that certain genes are methylated with high frequency in selected tumors, whereas others are methylated across most types of tumors. The objective of the work described below was to use global profiling platforms (RNA and DNA) to identify epigenetically modulated genes that may be involved in cancer pathogenesis and bring these to the point where they could be developed as targets for diagnostic and treatment strategies. Using a global expression profiling approach and pharmacological inhibition of the DNA methyltransferases, 132 genes were identified that have 5' CpG islands, are induced from undetectable levels by 5-aza-2'-deoxycytidine (5-aza) in multiple non-small cell lung cancer cell lines, and are expressed in untreated immortalized human bronchial epithelial cells. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (N=20) and adjacent non-malignant tissue showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. Promoter methylation of eight of these genes were studied in breast cancers (N=37), colon cancers (N=24), and prostate cancers (N=24) along with counterpart non-malignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. The data presented below suggest that while tumors differ in their molecular genetic phenotypes and pathogenesis, there may be underlying similarities in the pathways they follow toward malignancy. Some of these similarities may be reflected in the methylation programs tumor cells engage, which in turn, provides an opportunity to exploit for therapeutic applications and diagnosis. The approaches described herein entail a systematic and reproducible method to identify novel methylation markers in a variety of cancers, and the results of these studies provide a basis for developing a generic set of methylation markers for early detection screening across common epithelial cancers. en
dc.format.medium Electronic en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.subject Promoter Regions, Genetics en
dc.subject ATP-Binding Cassette Transporters en
dc.subject Gene Expression Profiling en
dc.subject Adenosine Triphosphate en
dc.title Aberrant DNA Methylation and Cancer: A Global Analysis of Promoter Hypermethylation in Human Lung Cancers en
dc.type.material Text en
dc.type.genre dissertation en
dc.format.digitalOrigin born digital en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph.D. en
thesis.degree.discipline Cell Regulation en
thesis.date.available 2007-12-20 en

Files in this item

Files Size Format View
shamesdavid.pdf 2.715Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record

Search DSpace


Advanced Search

Browse

My Account