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

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dc.contributor.advisor Minna , John D . en
dc.creator Shames , David S . en
dc.date.accessioned 2010 -07 -12T17 :37 :27Z en
dc.date.accessioned 2014 -02 -19T21 :59 :50Z
dc.date.available 2010 -07 -12T17 :37 :27Z en
dc.date.available 2014 -02 -19T21 :59 :50Z
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.genre dissertation en
dc.type.material Text en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph .D . en
thesis.degree.discipline Cell Regulation en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
dc.format.digitalOrigin born digital en
thesis.date.available 2007 -12 -20 en

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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 .

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