Exploring cancer biology using integrative genomics
Abstract/Contents
- Abstract
- Advances in genomic technologies have allowed investigators to survey diverse molecular properties of cancer cells including DNA copy number alterations, RNA transcript abundance, and protein-DNA binding events. While each data type offers a unique snapshot of the tumor cell, an integrated analysis of two or more complementary data types can reveal much more than the sum of its parts. In this dissertation, I describe new integrative genomic methodologies and novel biologic insights gleaned from their application. In one such analysis of 52 breast cancer cell lines, we identify genomic alterations and gene-expression profiles that largely resemble those identified in primary breast tumors, therefore defining relevant tumor models of breast cancer subtypes. Additionally, we identify 80 high-level DNA amplifications and 13 multi-copy deletions, harboring known and novel cancer genes, thereby providing a rich resource for new breast cancer gene discovery and characterization. In an integrative analysis of colorectal cancers, we unveil a region of amplification highly specific to colorectal-derived tumors. We identify and characterize caudal type homeobox transcription factor 2 (CDX2), a master regulator of intestinal cell survival and differentiation, as the target gene of this amplification, and show a CDX2 amplification-specific dependency for tumor cell survival, proliferation, and anchorage-independent growth. Moreover, by integrating protein-DNA binding and gene expression data, we uncover a novel relationship between CDX2 and Wnt/[beta]-catenin signaling. Taken together, these data show that for a subset of colorectal-derived tumors, cell survival and proliferation are dependent on the abnormal amplification and overexpression of CDX2, thereby characterizing CDX2 as a novel lineage-survival oncogene in colorectal cancer. In the last portion of the dissertation, I reflect on how the rapidly growing knowledgebase of genetic associations with disease and drug response will help usher in a new era of personalized medicine. To help prepare for a future that includes an array of available genomic laboratory tests, I discuss the necessity to reform medical school curricula to educate students about the interpretation, limitations, and impact of genomic testing in clinical medicine. I describe the challenges and considerations relevant to the development of a novel educational curriculum that includes personal genomic testing.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Salari, Keyan |
|---|---|
| Associated with | Stanford University, Department of Genetics |
| Primary advisor | Pollack, Jonathan R |
| Thesis advisor | Pollack, Jonathan R |
| Thesis advisor | Ford, James M. (James Matthew) |
| Thesis advisor | Sherlock, Gavin |
| Thesis advisor | Sidow, Arend |
| Advisor | Ford, James M. (James Matthew) |
| Advisor | Sherlock, Gavin |
| Advisor | Sidow, Arend |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Keyan Salari. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2011. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Keyan Salari
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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