Tag Archive for: aotw 17-07-19

Significant evidence is now emerging and publications have shown that the molecular characterization of tumours represents an important approach to stratifying patients with prostate cancer into appropriate treatments and their responses, helping to inform the next steps in the care pathway of these patients [1]. Understanding the functional role of the genes included in these signatures also gives an insight into the biology of the disease and how it develops and progresses.

BJUI has published papers in the past describing gene signatures that are associated with pathological Gleason score as pathological markers of aggressiveness and their potential role in predicting outcome [2].

The paper by Martini et al. [3] in the current issue of BJUI adds to this important literature. In a cohort of 159 patients, of whom 52 had tertiary pattern 5 (TP5) prostate cancer, Martini et al. showed that TP5 was associated with higher risk categories in the Decipher genomic score. Their study supports the literature showing that patients with TP5 have an elevated likelihood of developing disease after radical prostatectomy and have a poor prognosis [4]. It should be noted, however, that this is a small cohort with few patients defined as having TP5 disease. As prostate cancer is highly heterogeneous and gene expression can also be affected by the patient’s background, additional validation of this finding will be required in independent cohorts.

Additional analysis of the 698 gene by Martini et al. [3] identified a unique RNA signature of 18 genes for the TP5 cohort. A limitation of using the 698 gene previously demonstrated to be related to prostate cancer is that those with TP5 disease may be a unique subset of patients that may be associated with unfamiliar pathological pathways and new genes. An examination of novel genes whose expression pattern is unique to patients with TP5 disease may reveal additional genes.

Martini et al. then used the independent TCGA provisional database to link the expression of these 18 genes with clinical features. Patients harbouring any of the three genes CDKN2B, PLK1 and CDC20 mRNA were found to have worse progression‐free survival. The authors go on to undertake analysis of the 18 genes using the ingenuity network analysis tool identifying pathways involved in the cell cycle, DNA replication and repair, cellular assembly, cell death and survival and gene expression, which would fit with the biology of progressive disease. They also revealed a role in the dedifferentiation process and progression of cells towards anaplasia. They specifically identified CDKN2B, which has previously been associated with tumour suppression but might actually be linked to tumour progression, and identified it for further investigation.

Finally the researchers found that 13 genes out of the 18‐gene TP5 signature are upregulated in tumour lesions with TP5. Following these results they performed a sensitivity analysis in which the expression values of the genes in the cohort with GGG3‐4 and TP5 were compared with those of patients with GGG5 and discovered that these genes were similarly overexpressed in both groups. This finding strengthens the hypothesis that these genes are implicated in the dedifferentiation process of tumour cells, but it also raises the question of whether the pattern of expression of these genes is unique to patients with TP5 only, or whether it is associated with every tumour (primary, secondary or tertiary) that is classified as GGG5. Further research is needed to understand what the clinical significance of this genetic signature is and what pathological process it describes in practice.

This investigation into the functional role of the genes has given an insight into the biology of prostate cancer progression and TP5 disease which might inform a future area of research for novel biomarker panels and therapeutic interventions.

by R. William Watson and Omri Taltsh

References

1. Cucchiara, V, Cooperberg, MR, Dall’Era, M, Lin, DW, Montorsi, F, Schalken, JA, Evans, CP Genomic markers in prostate cancer decision making. Euro Urol 2018; 73: 572– 82
2. Pellegrini, K, Sanda, MG, Patil, D, Long, Q, Santiago‐Jiménez, M, Takhar, M, Erho, N, Yousefi, K,Davicioni, E, Klein, EA, Jenkins, RB, Karnes, RJ, Moreno, CS Evaluation of a 24‐Gene signature for prognosis of metastatic events and prostate cancer‐specific mortality. BJU Int 2017; 119: 961– 7
3. Martini, A, Wang, J, Brown, NM, Cumarasamy, S, Sfakianos, JP, Rastinehad, AR, Haines, KG,Wiklund, NP, Nair, SS, Tewari, AK A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome. BJU Int 2019; 124: 155– 62
4. Whittemore, DE, Hick, EJ, Carter, MR, Moul, JW, Miranda‐Sousa, AJ, Sexton, WJ Significance of tertiary Gleason pattern 5 in Gleason score 7 radical prostatectomy specimens. J Urol 2008; 179:516– 22