Genomic and mechanistic interrogation of novel genes and gene signatures in non-small cell lung cancer
Abstract/Contents
- Abstract
- Lung cancer is the leading cause of cancer deaths worldwide, with 1.7 million deaths per year. Moreover, lung cancer is comprised of several histological subtypes, with non-small cell lung cancer (NSCLC) making up ~85% of the cases. Presently, the most important prognosis of NSCLC is the stage of disease. However, a vast majority of patients have locally advanced or metastatic disease at the time of diagnosis. Despite the number of current therapies consisting of chemotherapy, radiation, and surgery, patients with locally advanced NSCLC have heterogeneous outcomes. Recently, the advent of targeted therapies against specific genetic mutations or rearrangements have improved response rates and overall survival but there remains an unmet need to uncover novel genes involved in this disease. We have applied bioinformatics approaches to better elucidate the role of various genes or gene signatures in non-small lung cancer in several capacities -- 1) to uncover gene expression signatures to improve risk stratification and outcome in those diagnosed with early stage NSCLC; 2) to identify de novo genomic fusions and breakpoints from targeted paired-end DNA sequencing data; and 3) elucidate the function of a novel splicing factor mutation in non-small cell lung cancer. In the first application, we obtained gene expression profiles from 1106 non-squamous NSCLCs for the generation and internal validation of a 9-gene molecular prognostic index (MPI). This was validated on an independent cohort of FFPE tissues from 98 NSCLC patients. As a second application, we demonstrate a practical and robust identification method of DNA rearrangements resulting in gene fusions through the development of a Fusion And Chromosomal Translocation Enumeration and Recovery Algorithm (FACTERA). Some of these recurrent fusions involving ALK, ROS1, RET, and NTRK1 have been identified in NSCLC, leading to the development and approval of targeted therapies. Lastly, the third application identifies a novel recurrent splicing factor mutation in non-small lung cancer. We have characterized the binding and splicing properties of this splicing factor and functional changes associated with the mutation. The approaches described here can be applied to uncover other gene or gene expression signatures in NSCLC and be expanded to other cancer indications.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lee, Luke Jaewon |
|---|---|
| Associated with | Stanford University, Cancer Biology Program. |
| Primary advisor | Alizadeh, Ash |
| Primary advisor | Diehn, Maximilian |
| Thesis advisor | Alizadeh, Ash |
| Thesis advisor | Diehn, Maximilian |
| Thesis advisor | Giaccia, Amato J |
| Thesis advisor | Pollack, Jonathan D |
| Advisor | Giaccia, Amato J |
| Advisor | Pollack, Jonathan D |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Luke Jaewon Lee. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Luke Jaewon Lee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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