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

Show full item record

Title: Aberrant DNA Methylation and Cancer: A Global Analysis of Promoter Hypermethylation in Human Lung Cancers
Author: Shames, David S.
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 .
URI: http : / /hdl .handle .net /2152 .5 /334
Date: 2006-12-20


Aberrant DNA Methylation and Cancer: A Global Analysis of Promoter Hypermethylation in Human Lung Cancers. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /334 .

Files in this item

Files Size Format View
shamesdavid.pdf 2.847Mb application/pdf View/Open

This item appears in the following Collection(s)

Show full item record

Search DSpace

Advanced Search