Year: 2016
Type: dissertation
Abstract: Cancer is a result of genetic and epigenetic aberrations acquired by somatic cells over time. Cancer genomes are littered with mutations, but only a few of them are considered ‘driver’ mutations essential for the development and progression of disease.\nIn spite of this complexity, many cancers are thought to be ‘oncogene addicts’: their survival and growth are dependent on the activity of a single oncogene. Pharmacological inhibition of such oncogenes, often tyrosine kinases, is a field of intense research activity. Tyrosine kinases are a class of proteins that, when constitutively activated, may contribute to carcinogenesis. This activation results from point mutations, overexpression, or chimeric gene fusions.\nFusion genes are caused by chromosomal rearrangements. Such aberrations have traditionally been detected and characterized by cytogenetic methods such as chromosome banding using Giemsa (G-banding) or other dyes and fluorescence in situ hybridization (FISH). After 2005, high-throughput nucleotide sequencing has enabled the large-scale detection of fusion genes in human cancer.\nEpendymal tumors are uncommon brain neoplasms affecting both adults and children. They are curable diseases mainly treated by surgery and radiotherapy. Chemotherapy has not yet proven effective and gross total tumor resection is the most important prognostic factor for ependymoma patients. Ependymomas are classified based on their histological characteristics, but the prognostic value of this classification system is controversial. The value of histological grading is particularly debated. Knowledge of ependymoma biology is an important key to better understanding of the tumors’ pathogenesis and to improve classification and prognostication. Importantly, such knowledge may also reveal novel potential treatment targets.\nThe overall aim of this thesis was to characterize the genomes and to search for the presence of fusion genes in ependymal tumors. The analyses were performed at the chromosomal, gene, and transcriptome levels, utilizing cytogenetic techniques (G-banding and comparative genomic hybridization) as well as high-throughput RNA sequencing and bioinformatic analyses.\nOur studies revealed that the chromosomal aberrations of the tumors we could study were mostly numerical in nature. Of the genomic imbalances present, complete or partial 6q loss was the most frequent. Four of the tumors harbored structural chromosomal rearrangements and two of these had a breakpoint in chromosome band 2p23.\nHigh-throughput RNA sequencing analysis revealed that both these tumors had rearrangement of the ALK gene which is located in chromosomal band 2p23. ALK is a receptor tyrosine kinase known to be crucial to the pathogenesis of several types of cancer. ALK fusions can be targeted specifically with several drugs, such as crizotinib and ceritinib. These are now in clinical use, especially in lung cancer treatment.\nFurther RNA-seq analyses revealed six additional cancer-specific chimeric transcripts in our series of ependymal tumors. These included recurrent CLU fusions in subependymoma. The fusions may be caused by hitherto undetected chromosomal aberrations or post-transcriptional (splicing) events, although we cannot rule out the possibility that they represent technical artefacts.\nWhole-genome sequencing in matched tumor and normal samples with subsequent structural variation analysis might shed light on the putative chromosomal aberrations underlying these chimeric transcripts. Finally, assuming that they are ‘true’ biological chimeras, it is unclear whether they represent driver or passenger events. Functional studies are needed to clarify the role of these fusions in ependymoma biology.
Author: Thale Kristin Olsen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2395304398