Assessment of the Utility of Gene Positioning Biomarkers in the Stratification of Prostate Cancers

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.