With PQDT Open, you can read the full text of open access dissertations and theses free of charge.
About PQDT Open
Search
Recent studies have shown that mutations at non-coding elements can act as cancer drivers. In this thesis, first, we describe CNCDriver (Cornell Non-coding Cancer Driver) algorithm that we have developed to analyze single nucleotide variants from large-scale cancer whole-genome sequencing data. Using this method, we identified drivers at protein-coding genes, promoters, enhancers, 5’UTRS, 3’UTRs, and ncRNAs. In particular, we propose CTCF insulators as a class of non-coding cancer drivers. We used insulator annotations from CTCF and cohesin ChIA-PET and analyzed somatic mutations in 1,962 whole-genomes from 21 cancer types. We find that mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation. Using CRISPR-Cas9 in human melanoma A375 cells, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40–50%, supporting the role of this boundary element as a cancer driver. Thus, our study reveals CTCF insulators as a novel class of putative non-coding cancer drivers. Overall, application of our method on non-coding elements reveals several novel putative drivers. Second, we describe CNCDatabase (Cornell Non-coding Cancer driver Database) in which we curated non-coding cancer drivers from published literature. CNCDatabase includes an interactive web interface from which the catalogue of drivers can be downloaded and the status of non-coding cancer drivers can be queried by gene name, or element type, or cancer type. Furthermore, the database is highly scalable to accommodate more non-coding cancer driver predictions. Overall, CNCDatabase provides a helpful resource for researchers to explore the pathological role of non-coding alterations and their associations with gene expression in human cancers.
Advisor: | Khurana, Ekta |
Commitee: | Leslie, Christina, Elemento, Olivier, Lipkin, Steven, Chi, Ping |
School: | Weill Medical College of Cornell University |
Department: | Physiology, Biophysics & Systems Biology |
School Location: | United States -- New York |
Source: | DAI-B 81/3(E), Dissertation Abstracts International |
Source Type: | DISSERTATION |
Subjects: | Genetics, Bioinformatics, Biology |
Keywords: | Cancer, CTCF, Driver |
Publication Number: | 13902177 |
ISBN: | 9781088302200 |