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dc.contributor.authorWilliams, Julia
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date2014-04-29 14:20:06.02en
dc.date.accessioned2014-04-29T20:27:47Z
dc.date.issued2014-04-29
dc.identifier.urihttp://hdl.handle.net/1974/12146
dc.descriptionThesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2014-04-29 14:20:06.02en
dc.description.abstractProstate cancer is a clinically heterogeneous disease, with manifestations ranging from a rapid and often fatal progression, to indolent disease. Unfortunately, current clinicopathological criteria cannot differentiate men whose tumours require immediate and aggressive therapy from those in which active surveillance may be more appropriate. Both PTEN deletion and ETS gene fusions are biomarkers with potential to aid in prostate cancer clinical management. In this thesis, I postulate that PTEN and fusion gene rearrangements may be associated with specific genomic changes, and might also have general impact on the genomic landscape of prostate cancer. A meta-analysis of somatic copy number alterations (CNAs) examined 662 unique prostate cancer patient samples consisting of 546 primary and 116 advanced tumours derived from eleven publications. Normalization, segmentation and identification of corresponding CNAs for meta-analysis were achieved using established commercial software. The CNA distribution in primary disease was characterized by losses at 2q, 3p, 5q, 6q, 8p, 12p, 13q, 16q, 17p, 18q and 10q (PTEN), and acquisition of 21q deletions associated with the TMPRSS2:ERG fusion rearrangement. Unsupervised analysis identified five genomic subgroups. Parallel analysis of advanced and primary tumours indicated that PTEN genomic deletions and the gene fusion were enriched in advanced disease. A supervised analysis of PTEN deletions and gene fusions demonstrated that PTEN deletion was sufficient to impose higher levels of CNA. Moreover, the overall percentage of the genome altered was significantly higher when PTEN was deleted, suggesting that this important genomic subgroup was likely characterized by intrinsic chromosomal instability. Candidate genes in each of the recurrent CNA regions characteristic of each subgroup showed that signalling networks associated with cancer progression and genome stability were likely to be perturbed at the highest level in the PTEN deleted genomic subgroup. Therefore classification of primary prostate cancer according to PTEN deletions, but not the gene fusion, was associated with greatly increased levels of CNA. Collectively, the impact of PTEN loss resulted in a significantly greater frequency and extent of alteration, and heightened genomic instability with concomitant pathway disruptions.en_US
dc.languageenen
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectcopy numberen_US
dc.subjectPTENen_US
dc.subjectgenomicen_US
dc.subjectTMPRSS2:ERGen_US
dc.subjectETS gene fusionsen_US
dc.subjectprostate canceren_US
dc.titleRECURRENT COPY NUMBER ALTERATIONS IN PROSTATE CANCER: THE GENOMIC IMPACT OF PTEN DELETIONS AND THE PROSTATE-SPECIFIC ETS GENE FUSIONSen_US
dc.typethesisen_US
dc.description.restricted-thesisOne manuscript is currently under review, once the manuscript has been published the restriction can be lifted.en
dc.description.degreePh.Den
dc.contributor.supervisorSquire, Jeremy A.en
dc.contributor.departmentPathology and Molecular Medicineen
dc.embargo.terms1825en
dc.embargo.liftdate2019-04-28


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