Molecular and Functional Consequences of Genetic Variability in the Ornithine Decarboxylase Gene in Colorectal Cancer

Persistent Link:
http://hdl.handle.net/10150/312735
Title:
Molecular and Functional Consequences of Genetic Variability in the Ornithine Decarboxylase Gene in Colorectal Cancer
Author:
Prieto, Jenaro Garcia-Huidobro
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release 14-Jan-2016
Abstract:
Dysregulation of cellular metabolism is associated with multiple diseases including cancer. Polyamines are organic cations shown to control gene expression at the transcriptional, post-transcriptional, and translational level. The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is associated with normal and neoplastic growth. A single nucleotide polymorphism (SNP, rs2302615, SNP +316 nucleotides 3' of the transcriptional start site) in the ODC1 gene has been found to be both functional and prognostic for risk of colorectal carcinogenesis. A comprehensive investigation of genetic variability in ODC1 gene was performed. We confirmed frequencies of 12 SNPs occurring in participants of a clinical cancer prevention trial. We identified haplotypes accounting for over 90% of the genetic diversity in the ODC1 gene. Mechanistically, we addressed two of them, which account for more than half of the participants in the clinical trial. Two ODC1 intron 1 SNPs, rs2302616 (SNP +263 nucleotides 3' of the transcriptional start site) and rs2302615, were found to be associated with disease processes. Both of them predicted metachronous adenoma and response to agents targeting the polyamine pathway in participants of the clinical trial. The rs2302616 functionally modulate a DNA G-quadruplex structure and predicted the ODC1 rate-limiting product putrescine by genotype. Both SNPs cooperate to modulate ODC1 transcriptional activity involving both a G-quadruplex structure and Sp1 binding site at rs2302616, and rs2302615 flanked MYC-binding E-boxes. Haplotype analysis, using both these SNPs, might provide better discrimination of both disease prognosis and treatment prediction in cancer chemoprevention clinical trials.
Type:
text; Electronic Dissertation
Keywords:
Genetic variability; G-quadruplex; ODC1 gene; Polyamine; SNP; Molecular & Cellular Biology; colorectal cancer
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Molecular & Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Gerner, Eugene; Thompson, Patricia

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleMolecular and Functional Consequences of Genetic Variability in the Ornithine Decarboxylase Gene in Colorectal Canceren_US
dc.creatorPrieto, Jenaro Garcia-Huidobroen_US
dc.contributor.authorPrieto, Jenaro Garcia-Huidobroen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseRelease 14-Jan-2016en_US
dc.description.abstractDysregulation of cellular metabolism is associated with multiple diseases including cancer. Polyamines are organic cations shown to control gene expression at the transcriptional, post-transcriptional, and translational level. The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is associated with normal and neoplastic growth. A single nucleotide polymorphism (SNP, rs2302615, SNP +316 nucleotides 3' of the transcriptional start site) in the ODC1 gene has been found to be both functional and prognostic for risk of colorectal carcinogenesis. A comprehensive investigation of genetic variability in ODC1 gene was performed. We confirmed frequencies of 12 SNPs occurring in participants of a clinical cancer prevention trial. We identified haplotypes accounting for over 90% of the genetic diversity in the ODC1 gene. Mechanistically, we addressed two of them, which account for more than half of the participants in the clinical trial. Two ODC1 intron 1 SNPs, rs2302616 (SNP +263 nucleotides 3' of the transcriptional start site) and rs2302615, were found to be associated with disease processes. Both of them predicted metachronous adenoma and response to agents targeting the polyamine pathway in participants of the clinical trial. The rs2302616 functionally modulate a DNA G-quadruplex structure and predicted the ODC1 rate-limiting product putrescine by genotype. Both SNPs cooperate to modulate ODC1 transcriptional activity involving both a G-quadruplex structure and Sp1 binding site at rs2302616, and rs2302615 flanked MYC-binding E-boxes. Haplotype analysis, using both these SNPs, might provide better discrimination of both disease prognosis and treatment prediction in cancer chemoprevention clinical trials.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectGenetic variabilityen_US
dc.subjectG-quadruplexen_US
dc.subjectODC1 geneen_US
dc.subjectPolyamineen_US
dc.subjectSNPen_US
dc.subjectMolecular & Cellular Biologyen_US
dc.subjectcolorectal canceren_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGerner, Eugeneen_US
dc.contributor.advisorThompson, Patriciaen_US
dc.contributor.committeememberGerner, Eugeneen_US
dc.contributor.committeememberThompson, Patriciaen_US
dc.contributor.committeememberCress, Anneen_US
dc.contributor.committeememberDoetschman, Tomen_US
dc.contributor.committeememberRogers, Gregoryen_US
dc.contributor.committeememberSchroeder, Joyceen_US
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