Abstract
There is a pressing need for additional clinical biomarkers to predict the aggressiveness of individual cancers. Here, we examine the potential usefulness of spatial genome organization as a prognostic tool for prostate cancer. Using fluorescence in situ hybridization on formalin-fixed, paraffin embedded human prostate tissue specimens, we compared the nuclear positions of four genes between clinically relevant subgroups of prostate tissues. We find that directional repositioning of SP100 and TGFB3 gene loci stratifies prostate cancers of differing Gleason scores. A more peripheral position of SP100 and TGFB3 in the nucleus, compared to benign tissues, is associated with low Gleason score cancers, whereas more internal positioning correlates with higher Gleason scores. Conversely, LMNA is more internally positioned in many non-metastatic prostate cancers, while its position is indistinguishable from benign tissue in metastatic cancer. The false positive rates were relatively low, whereas, the false negative rates of single or combinations of genes were high, limiting the clinical utility of this assay in its current form. Nevertheless, our findings of subtype-specific gene positioning patterns in prostate cancer provides proof-of-concept for the potential usefulness of spatial gene positioning for prognostic applications, and encourage further exploration of spatial gene positioning patterns to identify novel clinically relevant molecular biomarkers, which may aid treatment decisions for cancer patients.
Highlights
The genome is highly spatially organized within the interphase nucleus (Cremer and Cremer, 2001; Bickmore, 2013)
From that gene set we chose two genes, SATB1 and LMNA, for further assessment as potential biomarkers of high-risk prostate cancer because both genes repositioned in a single high-risk T3 stage cancer, but not in two intermediate risk T2 cancers, or a low risk T2 cancer (Leshner et al, 2016)
We selected SP100 to test its potential as a marker of low risk, since we previously found it to reposition in a low risk Gleason score 6 prostate cancer, but not in three intermediate or highrisk Gleason score 7 cancers (Leshner et al, 2016)
Summary
The genome is highly spatially organized within the interphase nucleus (Cremer and Cremer, 2001; Bickmore, 2013). Genes, and individual non-coding regions of the genome occupy preferred nuclear positions relative to the center of the nucleus or to other nuclear landmarks, such as associations with other genomic loci or nuclear bodies (Takizawa et al, 2008b; Bickmore and van Steensel, 2013; Meaburn, 2016). Some loci alter their position under different physiological conditions, for example, between cell/tissue types (Boyle et al, 2001; Parada et al, 2004; PericHupkes et al, 2010; Meaburn et al, 2016) or between different proliferation states (Bridger et al, 2000; Meaburn and Misteli, 2008; Chandra et al, 2015). Repositioning events are loci-specific and do not reflect global genome reorganization events (Meaburn, 2016)
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