Functional and genomic approaches in identifying new oncogenes and pathogens
CitationCai, Diana Qing. 2018. Functional and genomic approaches in identifying new oncogenes and pathogens. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractAdvances in genomics research over the past decade have expanded the possibilities for exploration across multiple fields of biology. Findings from genomic datasets, coupled with functional work, have enabled us to better understand the network of genes, RNA, proteins, non-coding elements, and other molecules that play a role in the basics of life. Two fields that have benefited immensely from the combined power of functional and computational genomics are cancer biology and infectious diseases.
We take advantage of observations stemming from genomic analyses of cancer samples to explore the functional consequences of putative oncogenic mutations. A recent exome sequencing study of lung adenocarcinoma patients who lack canonical oncogenic mutations revealed recurrent mutations of unknown functional significance in SOS1. We demonstrate that ectopic expression of SOS1 mutants confers oncogenic phenotypes both in vitro and in vivo and observe that these phenotypes are likely driven by over-activation of the Ras pathway. We also demonstrate that cancer cells with SOS1 mutations are dependent on SOS1 for growth and are sensitive to trametinib, a MEK inhibitor. Altogether, our findings provide experimental evidence for the role of SOS1 as a novel oncogene and suggest possible treatment avenues for SOS1-mutated cancers.
In addition to our functional study of SOS1, we describe a transcriptomic study of Kawasaki disease (KD) patients to better understand the underlying nature of the disease. Since its discovery in 1967, KD has been hypothesized to have an infectious origin; however, thus far, no single pathogenic agent has been definitively linked to the disease. Though we are unable to identify any clear, causal pathogens, we detect a variety of viruses, bacteria, and fungi from deep RNA sequencing of blood samples from KD and symptom-matched control patients. Through host transcriptome analysis, we observe an upregulation of heme metabolism, angiogenesis, and coagulation in KD samples. In these samples, transcriptome analysis also suggests an increase in neutrophil abundance, while immunogenomic profiling suggests depletion of T and B-cells. Overall, our results provide characterization of the microbial and immune populations present in the blood of KD patients and illuminate the potential processes involved in this disease.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41126795
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