On one of the prostate cancer dataset studied (obtained from a previous published study, [44] ), we observe a gradual pattern of reduction of Normalized Shannon Entropy from three well characterized tissue types: normal prostate, primary prostate tumours and lymph node metastases. On a different dataset on prostate cancer (from Ref [332] ), we observe that a group of samples having Gleason Figure 16 is that we have now highlighted the position of s ome probes which have been annotated as corresponding to ''non-coding RNAs''. In particular, we highlight those of MALAT1 (Metastasis associated lung adenocarcinoma transcript 1, (non-protein coding)), SNORA60 (small nucleolar RNA, H/ACA box 60); both increasingly downregulated, SNHG1 (small nucleolar RNA host gene 1 (non-protein coding)) and SNHG8 (small nucleolar RNA host gene 8 (non-protein coding)). The probes for MALAT1/MALAT-1 [742, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758] have a very conspiquous position, which we could judge a priori to be equivalent in relevance to those of the previously discussed roles of SFPQ, CD40, BRCA1, and TP53 (see Figure 16 ). MALAT1 has been recently pointed as a biomarker in primary human lobular breast cancer as a result of an analysis of over 132,000 Roche 454 high-confidence deep sequencing reads. Within the thousands of novel non-coding transcripts of the breast cancer transcriptome, Guffanti al., identified more than three hundred reads corresponding to MALAT1 [749] . This non-coding RNA, first identified in 2003 in non-small cell lung cancer, was shown to be highly expressed (relative to GAPDH) in lung, pancreas and prostate, but not in other tissues including muscle, skin, stomach, bone marrow, saliva, thyroid and adrenal glands, uterus and fetal liver (see figure four of Ref. [758] ). Our results indicate that the reduction of expression of some non-coding RNAs, in particular of MALAT-1, and SNORA60 with respect to their normal expression in prostate, as well as the upregulation of SNHG8 and SNHG1 should be monitored as useful biomarkers to track disease staging and progression to a more malignant phenotype. Interestingly enough, a study published in 2006 by Nadminty et al. has shown that KLK3/PSA modulates several genes, reporting a 16.5 fold downregulation of MALAT1 [810] . While these results have been obtained using the human osteosarcoma cell line SaOS-2, our results indicate that MALAT1 expression in the normal prostate and in cancer cells could also be considered as a relevant biomarkers to be tested in the future. doi:10.1371/journal.pone.0012262.g020 patterns 4 and 5 (two patterns which are typically associated to an aggressive phenotype) have lower Normalized Shannon Entropy values than a subset of Gleason pattern 3 (a pattern which is normally associated to a less aggressive phenotype but which nevertheless is still of clinical concern). However, a group of samples having Gleason patterns 3, 4, and 5 is revealed; this mixed cluster has a mid-range entropy. This is an interesting fact which correlates with the limitations observed in Ref. [332] . We note the authors' comment: ''We were unable to identify a cohort of genes that could distinguish between pattern 4 and 5 cancers with sufficiently high accuracy to be useful, suggesting a high degree of similarity between these cancer histologies or substantial molecular heterogeneity in one or both of these groups.'' Our results provide a conciliatory middle ground that explains the perceived clinical usefulness of Gleason pattern classification, widely used around the world, while at the same time reveals the reason for the difficulties of obtaining a good transcriptional signature for the other two patterns [791] .