Three-dimensional nuclear organization in cancer: examples from mouse plasmacytoma and human neuroblastoma
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Date
2017
Authors
Kuzyk, Alexandra
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Abstract
Three-dimensional (3D) nuclear organization is the study of the spatial distribution of nuclear contents and components. Aspects of nuclear organization that are examined in this thesis were chromosome territories, chromosomal sub-regions and telomeres.
We began by examining nuclear disorganization in a transgenic mouse model. Fast-onset PCTs, compared to slow-onset PCTs and wild-type mice, had higher numbers of telomeres and telomeric aggregates per cell, more short telomeres, an altered distribution of telomeres throughout the nucleus, and a larger nuclear volume (P < 0.0001).
We further examined this in a human context, looking for changes in nuclear organization in MYCN amplified compared to non-amplified neuroblastomas. Using dual-colored FISH and MYCN immunofluorescence on 16 neuroblastoma tissue samples, the unbalanced gain of 17q was found to be associated with high MYCN expression, no gain of 17q to be associated with medium MYCN expression, and numerical gain of chromosome 17 to be associated with low expression (P < 0.0001). The nuclear location of 17q also correlated with chromosome 17 copy number status. Telomere Q-FISH on 74 neuroblastoma tissue samples identified three tumor subgroups based on the measured telomere parameters, which represented unique levels of telomere dysfunction and genomic instability. Subgroups with higher levels of telomere dysfunction had more telomeres and telomeric aggregates per cell, and greater percentages of short and long telomeres (P < 0.0001); these subgroups also were associated with poor prognostic clinical features (P < 0.001).
This thesis illustrates the significance of multiple parameters of 3D nuclear organization in both PCT and neuroblastoma. The changes observed in the nuclear architecture of these cancers reflect increased telomere-mediated genomic instability that is driven by MYC and MYCN. Furthermore, the differences between aggressive and less-aggressive forms of the tumors suggest 3D nuclear organization could be used as a novel biomarker in cancer.
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Nuclear architecture