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S. K. Houston, Y. Pina, W. K. Scott, L. Nathanson, A. C. Schefler, T. G. Murray; Regional and Temporal Differences in the Genetic Expression of LHBetaTAg Retinoblastoma Tumors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2066.
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Molecular genetic analysis has shown significant potential in the evaluation and potential therapeutic approaches for a variety of malignancies. In this study, we characterized the regional and temporal genomic differences in LHBETATAG retinoblastoma tumors using genetic microarray. This study establishes a framework to evaluate treatment influences on a molecular level in advancing retinoblastoma.
Transgenic mice with documented intraocular tumor were sacrificed and enucleated at 12, 16, and 20-weeks in age (n=9). A molecular genomics array analysis was performed investigating temporal variations and regional differences within each individual tumor. RNA was isolated, amplified, and sense-strand cDNA was created. Samples were hybridized with Affymetrix arrays, and scanned using Affymetrix GeneChip scanner. Raw data was normalized and general linear models were used to examine expression differences by tumor development and region. Significance of expression differences was determined using a false discovery rate (FDR) of 5% to correct for multiple comparisons.
There are significant temporal differences in the apical regions of 12-week to 20-week LHBETATAG retinoblastoma tumors (p < 0.001, FDR < 0.05, two-way analysis of variance, ANOVA, general linear models procedure). Analysis shows a greater than 2-fold up-regulation of 365 genes in the advanced tumors (20-week) compared to early tumors (12-week) in the apical regions. Three genes were consistent in their changes between 20 versus 12-weeks and 16 versus 12-weeks, including Olfr124 (-2.0 and -1.8 fold change), Pisd (-1.4 and -1.4 fold change), and Csnk2a2 (2.5 and 2.2 fold change). Additionally, the gene Mmu-mir685 is differentially expressed between 16 and 12-weeks (11 times under-expressed). Regional variations within individual tumors were noted, particularly prominent between tumor center and apex.
The current study illustrates that temporal variations in genetic expression in LHBETATAG retinal tumors exist and documents intratumoral regional genomic variation corresponding to areas of local heterogeneity in the tumor microenvironment. These results indicate that advancing tumors undergo selective genetic alteration to drive further growth and progression. The up-regulated genes involved in key cellular pathways are potential targets for future adjuvant therapies.
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