Title

Mitochondrial Genetics and Function among Men Screened for Prostate Cancer

Date of Award

12-1-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Arthur J. Eisenberg

Second Advisor

Rhonda Roby

Third Advisor

Robert C. Barber

Abstract

Genetic alterations are associated with sporadic cancer development, progression and metastasis. Until now, more was known about nuclear DNA (nDNA) mutations and their role in cancer than the types of genetic changes that occur in the mitochondrial genome (mtGenome). Changes to mitochondrial DNA (mtDNA) are frequent in prostate cancer (PCa). Further, these changes have been associated with enhanced tumorigenesis and progression to an aggressive phenotype. However, it is unclear whether changes to the mtGenome can delineate PCa progression from indolent cancer to an advanced metastatic disease. An exhaustive characterization of the mtGenome of men screened for PCa was performed to determine if genetic differences between varying PCa disease states can be measured.

Two genetic techniques (copy number and genome sequencing) were used to perform a comprehensive characterization of the changes to mtDNA in whole blood extracts from three groups of men screened for prostate cancer: normal control (NC), no evidence of disease (NED), and, biochemical recurrence/metastasis (BCR/MET). Mitochondrial DNA copies per cell and mtGenome deletion ratio (whole mtGenomes:truncated mtGenomes) were measured using a multiplex real-time quantitative PCR (qPCR) assay. Whole mtGenome sequence data were generated using a massively parallel sequencing platform, the Ion Torrent Personal Genome Machine (PGM).

Real-time qPCR revealed a higher dispersion of mtDNA copies per cell and mtGenomes harboring a large scale deletion in samples from men with advanced stages of PCa when compared to normal controls and indolent PCa. Whole mtGenome sequencing showed a higher number of genetic variants in men with PCa, some of which are predicted to be pathological. A significant positive correlation was observed between mutational load and PCa disease status. Further, three-dimensional comparative modeling evidenced the negative effect of a single mtDNA missense mutation on a protein’s structural integrity. Overall, the presented data suggest there are differences in the mtGenome between men with and without PCa that are measurable in peripheral blood and may be used as a potential risk assessment tool. Future analyses with a larger sample size may lead to more compelling evidence that supports the role of changes to the mtGenome with PCa progression.

Comments

Sprouse, Marc L., Mitochondrial Genetics and Function among Men Screened for Prostate Cancer. Doctor of Philosophy (Biomedical Sciences, Molecular and Medical Genetics), November 2015, 178 pp., 15 tables, 33 illustrations, bibliography, 303 titles. Available December 2016.

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