Clinical significance of p53 alterations in surgically treated prostate cancers

Abstract

Despite the high number of previous studies, the role of p53 alterations in prostate cancer is not clearly defined. To address the role of p53 alterations in prostate cancer biology, a total of 2514 cancers treated by radical prostatectomy were successfully analyzed by immunohistochemistry in a tissue microarray format. Overall a low rate of p53-positive tumors was found (2.5%). A significant underestimation of p53-positive cases was excluded by subsequent large section analyses and direct sequencing of the p53 gene in subsets of our patients. Large section analysis of 23 cases considered negative on the tissue microarray yielded only one weakly p53-positive tumor. Only 4 out of 64 (6.4%) high-grade tumors, that were considered negative for p53 by immunohistochemistry, presented exon 5-8 mutations. These data suggest a high sensitivity of our immunohistochemistry approach and confirm the overall low frequency of p53 alterations in clinically localized prostate cancer. A positive p53 immunostaining was strongly associated with presence of exon 5-8 mutations (Po0.0001), advanced pT-stage (Po0.0001), high Gleason grade (Po0.0001), positive surgical margins (P ¼ 0.03) and early biochemical tumor recurrence (Po0.0001). A higher rate of positive p53 immunostaining was detected in late-stage diseases including metastatic prostate cancer (P ¼ 0.0152) and hormone-refractory tumors (P ¼ 0.0003). Moreover, p53 expression was identified as an independent predictor of biochemical tumor recurrence in the subgroup of low-and intermediate-grade cancers. In summary, the results of this study show that p53 mutations characterize a small biologically aggressive subgroup of prostate cancers with a high risk of progression after prostatectomy. The rate of p53 alterations increases with prostate cancer progression.

Molecular classification of prostate cancer using curated expression signatures

“…This result may have technical reasons (small signature size) or may be related to the earlier age of diagnosis in this cohort (as P53 mutations are known to be late events in prostate cancer) (22,23). A TMPRSS2-ERG fusion group, a differentiated PRC2 group, and one Cytokine | Transitional group-which can be compared with an admixture of the Cytokine | RAS | Mesenchyme and the transitional subtypes within the first dataset (the algorithm may collapse clusters in smaller datasets due to Bayesian optimization)-reemerged with highly comparable molecular characteristics.…”

“…This fusion of an androgen-responsive promoter with the ERG transcription factor (an ETS family member) may lead to increased cell migration (18), promotion of an epithelial-mesenchyme transition (EMT), and proliferation (18)(19)(20)(21), but the details remain unclear. P53 mutations have been reported in 3-20% of prostate cancers at diagnosis (22)(23)(24) and are often correlated with tumor recurrence, castration resistance, and grade of the tumor (22,23). Overexpression of MYC due to amplifications has also been observed in a fraction of prostate tumors, leading to increased proliferative signals (24)(25)(26).…”

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

“…In breast carcinoma, for example, molecular profiling revealed four major subtypes displaying variable frequencies of TP53 mutations: 12%, 30%, 72%, and 80% for the luminal A, luminal B, HER2-E, and basallike subtypes, respectively (Weigelt et al 2010;Curtis et al 2012). Considering the stage of development, a lower frequency of TP53 mutations was reported in primary prostate tumors (between 10% and 20%) than in metastatic tumors (up to 50%) (Schlomm et al 2008). In biphasic chronic myeloid leukemia, TP53 mutations most frequently occur during the blastic phase (Calabretta and Perrotti 2004;Malcikova et al 2014).…”

The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

“…All prostate specimens were analyzed according to a standard procedure, including a complete embedding of the entire prostate for histological analysis. 20 The TMA manufacturing process was described earlier in detail. 21 In short, one 0.6 mm core was taken from a representative tissue block from each patient.…”