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GENOMIC RISK FACTORS ASSOCIATED WITH EWING SARCOMA SUSCEPTIBILITY
by
Melissa Brooke Warden
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSPHY
(MOLECULAR EPIDEMIOLOGY)
May 2012
Copyright 2012 Melissa Brooke Warden
Object Description
| Title | Genomic risk factors associated with Ewing Sarcoma susceptibility |
| Author | Warden, Melissa Brooke |
| Author email | mwarden@usc.edu;melissawarden@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Epidemiology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-03-15 |
| Date submitted | 2012-05-04 |
| Date approved | 2012-05-04 |
| Restricted until | 2012-05-04 |
| Date published | 2012-05-04 |
| Advisor (committee chair) |
McKean-Cowdin, Roberta Gauderman, W. James |
| Advisor (committee member) |
Asgharzadeh, Shahab Triche, Timothy Ingles, Sue |
| Abstract | Ewing Sarcoma (EWS) is malignant tumor of bone or soft tissue that primarily affects children and adolescents. Most EWS tumors share the oncogenic fusion protein EWS-FLI1 which is thought to play a role in the pathogenesis of these tumors. Besides age, gender, and race, few environmental or genetic risk factors have been identified that explain a substantial proportion of EWS cases. However, the ethnic-specific differences in incidence of EWS suggest a genetic predisposition may be an important determinant of developing this disease. In this dissertation, we hypothesized that genomic risk factors are associated with risk of developing EWS. Specifically we will identify single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with EWS using a family-based genome-wide association study (GWAS) design. In the initial GWAS discovery phase, we identified several potential SNP variants associated with EWS. For replication we selected the top 30 most significant SNPs with differences in allele frequencies across racial ethnic groups with known differences in risk of EWS. We identified 2 SNPs associated with EWS (p-value < 0.05) in a combined analysis of the discovery and replication sets. First, SNP rs11217524 was associated with EWS using a joint case-control analysis (OR = 0.48, 95% CI = 0.33 - 0.71, p-value = 1.6X10⁻⁴) and joint transmission disequilibrium test (TDT) analysis (OR = 0.63, 95% CI = 0.40 - 1.00, p-value = 5.0X10⁻²). SNP rs11217524 is located near poliovirus receptor-related 1 (PVRL1) on chromosome 11q23.3. This gene encodes an adhesion protein that is used as a receptor for herpes simplex virus to mediate entry of the virus into human epithelial and neuronal cells. Second, SNP rs7907995 was also associated with EWS using a joint case-control analysis (OR = 1.36, 95% CI = 1.05 - 1.78, p-value = 2.2X10⁻²) and joint TDT analysis (OR = 1.57, 95% CI = 1.03 - 2.78, p-value = 3.1X10⁻²). SNP rs7907995 is located near the ankyrin repeat domain-containing protein 30A (ANKRD30A) gene on chromosome 10p11.21. This locus is also known as NY-BR-1 or antigen B726P, which has been used as a biomarker of disseminated breast cancer cells. The associations of these 2 candidate SNPs and differences in allele frequencies across different ethnic populations suggest that risk variants on chromosomes 10 and 11 may contribute to the ethnic-specific incidence pattern of EWS. A family-based CNV association analysis of 22,543 probes in the 27 case-parent trios also provided suggestive evidence that chromosomal region 14q11.2 may be associated with EWS risk (p-value = 4.0X10⁻⁴). Several probes in this region are located within the heterogeneous nuclear ribonucleoprotein C (HNRNPC) gene. This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs), which affect pre-mRNA processing and other features of mRNA metabolism and transport. The potential for early detection of EWS by screening children for a marker of genetic susceptibility to this disease could improve diagnosis and treatment of future patients. Given the small sample size of this study, replication in a larger dataset is needed to confirm these candidate genomic markers. |
| Keyword | single nucleotide polymorphism; copy number variation; genome-wide association study; Ewing Sarcoma |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Warden, Melissa Brooke |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-WardenMeli-750.pdf |
Description
| Title | Page 1 |
| Full text | GENOMIC RISK FACTORS ASSOCIATED WITH EWING SARCOMA SUSCEPTIBILITY by Melissa Brooke Warden A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSPHY (MOLECULAR EPIDEMIOLOGY) May 2012 Copyright 2012 Melissa Brooke Warden |
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