Identification Of Novel Epigenetic Biomarkers For Early Detection In Various Cancer Types

IDENTIFICATION OF NOVEL EPIGENETIC BIOMARKERS FOR EARLY DETECTION IN VARIOUS CANCER TYPES Santosh Mahadevana Goud, PhD George Mason University, 2017 Dissertation Chair: Dr. Serguei G. Popov Epigenetic landscape of cancer cells undergoes profound and significant changes during the development of human malignancies. In fact, global changes in the epigenetic landscape are a hallmark of cancer. Histone modifications and DNA methylation are prominent among such changes. The genome undergoes a large-scale DNA methylation changes alongside other alterations in a collective events of post-translational chromatin modifications being observed. Such aberrant epigenetic changes have a high impact at various stages of tumorigenesis. Identification of such epigenetic aberrations for their use as predictive and prognostic biomarkers has been the focus of cancer genomics research recently. We have selected five genes of interest (ITPKA, GDF15, BLCAP, PIWIL4 and DMRT1) based on literature search and identified each of them as novel epigenetic biomarkers in certain cancer types. Such identified novel epigenetic methylation biomarker gene is subjected to SNV identification by querying it against BioMuta and analyzing its relevant phenotypic effects. BioMuta is a curated single-nucleotide variation (SNV) and disease association database. Here, the variations are mapped to the genome/protein/gene. Such query helps to identify variations and since the database is compiled from various sources through bio curation, it paves ways for prioritizing variations for further experimental evaluations. Furthermore, such identified epigenetic methylation biomarker gene is subjected to gene expression analysis by querying it against BioXpress database. BioXpress is a curated gene expression and disease association database. Here, the expression levels are mapped to genes. BioXpress is useful in identifying differences between expression levels in disease and normal pairs and to discover differential expression for a gene. It also helps in identification of potential biomarkers or pathways that lead to tumor formation or to explore the overall expression of specific genes across multiple cancer types. Upon additional validations, these findings on novel epigenetic methylation biomarker gene will possibly open new avenues in translation medicine and can be utilized as a novel prognostic biomarker for early stage cancer detection. Chapter 1: INTRODUCTION 1.1 Hypothesis, rationale, and specific aims The literal meaning of the term epigenetics is in addition to changes in genetic sequence. In other words, any process that has the capability to alter gene activity without any accompanying changes in DNA sequence, leading to modifications that are transmitted to daughter cells can be defined as an epigenetic change. However, it is been shown that some epigenetic changes can be reversed. The exact definition and/or meaning of the term epigenetic is still debatable and undergoing constant changes. Epigenetic processes identified till date involves/ includes: methylation, acetylation, phosphorylation, ubiquitylation and sumolyation. Epigenetic processes are natural and in many cases are essential to normal organism functioning. However, in certain cases, it seems to show some major adverse health and behavioral effects. DNA methylation is a well-studied and well-documented epigenetic process. It involves addition or removal of a methyl group (CH3), predominantly at sites where cytosine bases occur consecutively. This event was first documented in 1983 and has been continuously monitored and found in many disease and health disorders. Chromatin modification is yet another epigenetic process. Chromatin is DNA and proteins (histones) complex which is highly compacted into the nucleus. Chromatin complex is modified by processes like acetylation (addition of acetyl groups), enzymes and certain RNAs (micro and small interfering RNAs). These modifications can influence gene expression by directly altering the chromatin structure. Highly compacted and condensed chromatin does not allow expression, whereas unfolded or open chromatin structure is functional and allows or facilitates gene expression to take place.