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J. Harbour, L. A. Worley, J. Ehlers, M. D. Onken; Prognostically Relevant Molecular Classification of Uveal Melanoma Based on Integrative Genomic Analysis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1505.
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Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. Uveal melanoma exhibits a discrete spectrum of chromosomal alterations as well as random background aneuploidy. This study explored the prognostic value of recurrent chromosomal alterations versus overall aneuploidy, and the relationship of these chromosomal changes to an established molecular classification of uveal melanoma based on gene expression profile (GEP).
Genomic DNA copy number analysis using comparative genomic hybridization, and GEP using microarray chips in 49 of our primary uveal melanomas. Meta-analysis of cytogenetic findings in 336 published primary uveal melanomas.
Four prognostically significant sub-classes were identified: (1) GEP class 1 with minimal aneuploidy, (2) GEP class 1 with 6p gain, (3) GEP class 2 without 8p loss, and (4) GEP class 2 with 8p loss. Mathematical modeling suggested that these discrete patterns of genomic alterations accumulated in a discrete temporal sequence. A gene expression signature associated with overall aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P=0.003). Clinical outcome was more closely associated with discrete chromosomal alterations than overall aneuploidy.
We propose a more detailed version of our previous molecular classification of uveal melanoma by combining GEP and chromosomal data. This classification accurately predicts metastasis-free survival time and may reflect a temporal sequence in tumor progression. The role of PTEN and other genomic integrity regulators in tumor progression requires further investigation as potential therapeutic targets.
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