Chromosomal Basis of Prostate Cancer Oncogenesis
Ben Beheshti
Supervisor: Dr. Jeremy Squire
Doctor of Philosophy, 2003
Department of Laboratory Medicine and Pathobiology
University of Toronto
(Defended November 4, 2002)


Prostate cancer (CaP) is the leading cancer incidence in men in North America. While the etiology of CaP remains unknown, both environmental or epigenetic and genetic contributions have been associated with its carcinogenesis. Diagnosis and clinical disease management is complicated because CaP is characterized by multifocal presentation and phenotypic and genotypic heterogeneity. Consequently, the current phenotype-based histologic grading system fails to discriminate between tumour subpopulations of intermediate grade with different disease potential. The molecular model of CaP progression from initial normal dysplasia to terminal late-stage metastatic disease suggests that the progression is in incremental steps involving multiple genetic alterations. This conceptual model is based on a limited amount of data and does not adequately account for the genotypic heterogeneity and multifocality evident in CaP. To improve our knowledge of the chromosomal changes associated with CaP oncogenesis, advanced molecular cytogenetics methods were used to define the cellular and cytogenetic heterogeneity present in CaP. Spectral karyotyping (SKY) analysis of virus-immortalized CaP cell lines derived from early-stage tumours suggested that loss of chromosome 8p and gain of 8q were initial critical events in CaP tumourigenesis. SKY and fluorescence in situ hybridization analyses of established CaP cell lines also showed rearrangements of chromosome 8, a high frequency of centromeric rearrangements, together with spontaneous de novo structural and numerical rearrangements. Comparative genomic hybridization (CGH) following laser capture microdissection of a series of individual CaP microfoci identified distinct chromosomal copy number changes in each focus. However, the majority of foci had acquired changes of chromosome 8, often by different chromosomal mechanisms. Interphase FISH analysis of CaP cell lines and primary tumour cytogenetic preparations also suggested that chromosome 8 aneusomy was common, and implicated that numerical change arose because chromosomal segregation mechanisms were perturbed. Overall, these results underscore the importance of chromosome 8 alterations in CaP oncogenesis and implicate chromosomal instability as a mechanism for the generation of a high frequency of potentially adaptive alterations. These findings provide additional support for the genotyping heterogeneity that characterizes CaP in keeping with a model that invokes a polyclonal origin for CaP with multifocal presentation.

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© Ben Beheshti, 2002-2003.