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Title page for ETD etd-05242017-171945

Type of Document Dissertation
Author O'Brien, Timothy Daniel
Author's Email Address timothy.obrien@vanderbilt.edu
URN etd-05242017-171945
Title Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer
Degree PhD
Department Human Genetics
Advisory Committee
Advisor Name Title
David Samuels Committee Chair
Jirong Long Committee Member
John A. Capra Committee Member
Melinda Aldrich Committee Member
Nancy Cox Committee Member
Zhongming Zhao Committee Member
  • RNA-Seq
  • WES
  • somatic mutations
  • differential expression
  • enhancer
  • eQTL
  • lung cancer subtypes
  • GWAS
Date of Defense 2017-03-06
Availability restricted
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.
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