Lung cancer is classified into two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has several subtypes, but the two most commonly occurring subtypes are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These classifications are mostly based upon histological and pathological characteristics, but there is increasing evidence of genetic and molecular differences as well. Although previous work has identified differences between subtypes of NSCLC at the somatic level, little work has been done to look at differences in all three subtypes across both the germline and somatic genomes. I hypothesized that a comprehensive detailed comparison of these lung cancer subtypes at both genomes would reveal shared and distinct mechanisms of disease. In this work, I used single nucleotide polymorphisms (SNPs) identified as significant (p < 1 x 10-3) in a genome wide association study (GWAS) to identify regulatory variants associated with each lung cancer subtype. I used these regulatory SNPs to identify sets of regulated genes in the genome for each subtype. I also expanded this germline work across other lung diseases and cancer types to extend the utility of the pipeline. At the somatic level, I identified genes that were differentially expressed in lung tumor versus normal tissue. Additionally, I identified mutational signatures and sets of potential driver genes in the somatic genomes for each subtype. I also identified biological pathways enriched with the germline and somatic gene sets. Finally, I performed a detailed comparison of calling somatic single nucleotide variants (SNVs) from whole exome sequencing (WES) versus transcriptome sequencing (RNA-Seq) in NSCLC. Overall, across all comparisons and genomes, I observed very little overlap between the three lung cancer subtypes. However, I found one gene, CHRNA5, disrupted by regulatory variants in the germline genomes and differentially expressed in the somatic genomes. This gene encodes a nicotinic acetylcholine receptor and may play a role in lung cancer due to its finding across both genomes and all three subtypes.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-05242017-171945 |
| Date | 26 May 2017 |
| Creators | O'Brien, Timothy Daniel |
| Contributors | David Samuels, John A. Capra, Melinda Aldrich, Jirong Long, Nancy Cox, Zhongming Zhao |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-05242017-171945/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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