Integrative analyses of hippo pathway Mutations in human cancer genome
Open Access
- Author:
- Yu, Tian
- Graduate Program:
- Molecular, Cellular and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 29, 2014
- Committee Members:
- Zhi Chun Lai, Dissertation Advisor/Co-Advisor
Zhi Chun Lai, Committee Chair/Co-Chair
Francisco Javier Diaz, Committee Member
Graham Hugh Thomas, Committee Member
Robert Paulson, Special Member - Keywords:
- mutation
cancer genome
Hippo Pathway
signal transduction
tumor
mutation correlation - Abstract:
- Cancer genome projects identified somatic mutations in Hippo pathways; however, their functional impacts and association with other mutated genes in the signal transduction network is elusive. In this dissertation, I have analyzed the somatic non-synonymous mutations of Hippo Pathway core components, which regulates organ size and tumorigenesis in Drosophila and mammals. First, I used LATS1/2 as an example to evaluate the potential functional importance of mutated residues of Hippo pathway tumor suppressors in human cancers. The study identified the loss-of-function mutations of LATS1 and LATS2 alleles from human cancer, which promote tumor development. Second, the mutation spectra of Hippo Pathway core components (LATS1/2, STK3/4, TEAD2/4, YAP and WWTR1) have been explored based on mutation pathogenicity tools and literature for their domains and functional partners. Last, my genomic analyses focuses on the concurrent and mutually exclusive gene relationship between Hippo pathway mutations and the other gene mutations in cancer. The significant mutated genes are analyzed in the patient pools with damaging mutations from each of the Hippo pathway components alongside sets of non-damaging controls. Significant concurrent and mutually-exclusive relationships were revealed among the mutations of cancer census genes and the interactome of the Hippo core components. The unbiased screening selected a list of genes with strong associations with Hippo components. These work pushed the limit of previous work, and shed light on the mechanisms of Hippo pathway and the development of hippo pathway related diagnostic biomarker panel.