Semester

Spring

Date of Graduation

2003

Document Type

Dissertation

Degree Type

PhD

College

Davis College of Agriculture, Natural Resources and Design

Department

Biochemistry

Committee Chair

Joginder Nath.

Abstract

Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor have consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We further defined cytogenetic abnormalities of this tumor using molecular cytogenetic techniques on 10 uveal malignant melanoma cell lines and 100 formalin-fixed paraffin-embedded (FFPE) tumors.;The synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement plays a significant role in the generation of DNA sequence copy number abnormalities throughout the genome, but none of the cell lines demonstrated monosomy 3. Centromeric fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately one signal per cell, but further evaluation with telomeric probes demonstrated multiple signals per cell, suggesting chromosomal rearrangement without the loss of an entire chromosome 3. Based on combined CGH, SKY and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements rather than whole-chromosome loss in uveal melanoma.;CGH was similarly employed to elucidate characteristic DNA-sequence copy number abnormalities of FFPE archival cases of uveal melanoma, and correlate genomic imbalance abnormalities with a prognosis. We set out to study 100 archival uveal melanoma cases, each with comprehensive patient follow-up, by correlation of copy number imbalances with survival. Fifty-one patients survived more than 9 years without evident metastasis, and the remaining 49 patients died with metastatic disease. Viable probe was generated from 82 of the 100 cases, allowing correlation of CGH findings with patient histories for all but 18 of the cases. Significant copy number imbalances were tested for univariate prognostic significance. The most powerful predictor of prognosis was gain of 18q11.2, which was subsequently compared with other significant chromosomal regions, as well as histological and clinical factors in a multivariate analysis. Multivariate analyses revealed that the gain of 18q11.2 and concomitant loss of 1p33 was the strongest indicator of a poor prognosis.;Our large-scale molecular cytogenetic analysis of cell lines and archival material contributes significantly to the characterization of uveal melanoma. This research is intended to direct further gene-specific study of malignancy in uveal melanoma.

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