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Comparative genome-wide DNA methylation studies of healthy human tissues
and non-small cell lung cancer tisuse
Kaie Lokk
Methylated cytosines have a crucial role in mammalian development, and the proportion of
methylated CpG sites can vary greatly over a genome. As DNA methylation is vital for the normal
functioning of organism, changes in the epigenome can account for individual differences in drug
responses or the incidence of severe diseases, especially cancer.
The aim of the experimental work presented in this thesis was to describe methylation patterns and
their effect on gene expression in different tissue types, both healthy and cancerous. Studies of
healthy human tissues confirmed a clear correlation between DNA methylation in promoter
regions and gene expression. The DNA methylation patterns also clearly reflected tissue-specific
functions as demonstrated with hierarchical clustering and GO analyses of hypomethylated tissuespecific differentially methylated regions (tDMRs). The tDMR analysis revealed that a large
number of methylated regions were within gene body regions, yet we were not able to show how
these tDMRs mechanistically contribute to tissue-specific functions.
Based on the observation that inter-individual variability in ADME gene expression affects drug
efficacy, toxicity, and susceptibility to environmental toxins, we determined to what extent SNPs
and DNA methylation can jointly explain variations in ADME gene expression in liver. As
expected, the combination of SNP genotype and CpG site methylation levels data explained more
of the observed expression variations than the use of SNP or methylation levels alone.
The last part of the thesis concentrated on describing DNA methylation patterns in early-stage nonsmall cell lung cancer (NSCLC) patients. A number of differentially methylated CpG sites were
found, most of the identified genes represent novel markers for NSCLC. GO analysis revealed that
differentially methylated genes were closely related to cancer progression. Furthermore, a survival
analysis identified a number of CpG sites whose methylation levels differed according to patient
survival. Accordingly, the latter sites represent CpGs that could potentially serve as prognostic