Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation.

P53 immunohistochemistry (IHC) has been proposed as a surrogate for TP53 mutations in penile squamous cell carcinomas (PSCC). We aimed to evaluate the performance of a pattern-based evaluation of p53 IHC in PSCC. Human papilloma virus (HPV) DNA testing, p16 and p53 IHC, and whole exome sequencing were performed in a series of 40 PSCC. p53 IHC was evaluated following a pattern-based framework and conventional p53 IHC evaluation. Out of 40 PSCC, 12 (30.0%) were HPV-associated, and 28 (70.0%) were HPV-independent. The agreement between the p53 IHC pattern-based evaluation and TP53 mutational status was almost perfect (k = 0.85). The sensitivity and accuracy of the pattern-based framework for identifying TP53 mutations were 95.5% and 92.5%, respectively, which were higher than the values of conventional p53 IHC interpretation (54.5% and 70.0%, respectively), whereas the specificity was the same (88.9%). In conclusions, the pattern-based framework improves the accuracy of detecting TP53 mutations in PSCC compared to the classical p53 IHC evaluation.

The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and non-progressive ccRCCs using Illumina Hi-seq 4000. Differentially expressed genes (DEG) were intersected with the RNA-sequencing data from the TCGA. The overlapping genes were used for further analysis. A total of 132 genes were found to be prognosis-related genes. LASSO regression enabled the development of the best prognostic six-gene panel. Cox regression analyses were performed to identify independent clinical prognostic parameters to construct a combined nomogram which includes the expression of CERCAM, MIA2, HS6ST2, ONECUT2, SOX12, TMEM132A, pT stage, tumor size and ISUP grade. A risk score generated using this model effectively stratified patients at higher risk of disease progression (HR 10.79; p < 0.001) and cancer-specific death (HR 19.27; p < 0.001). It correlated with the clinicopathological variables, enabling us to discriminate a subset of patients at higher risk of progression within the Stage, Size, Grade and Necrosis score (SSIGN) risk groups, pT and ISUP grade. In summary, a gene expression-based prognostic signature was successfully developed providing a more precise assessment of the individual risk of progression.

Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with treatment resistance, worse survival, and aggressive variants of prostate cancer (AVPC). We previously developed and validated a signature reflecting low TSG expression (TSG_low) that was associated with poor outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) ± docetaxel. The aim of this multicenter retrospective study was to validate the TSG_low signature in patients with mHSPC treated with ADT and an androgen receptor pathway inhibitor (ARPI) and to explore clinical characteristics at progression according to TSG status. TSG mRNA expression in formalin-fixed, paraffin-embedded samples was assessed via nCounter. Correlation of expression levels with castration-resistant prostate cancer–free survival (CRPC-FS; primary endpoint) and overall survival (OS) was investigated via Kaplan-Meier and multivariate Cox analyses. Of the 137 patients included, 77.4% had de novo stage IV cancer and 44.5% had high-risk disease. TSG_low (16.8%) was correlated with visceral metastases (p = 0.013), high-risk disease (p = 0.038), higher Gleason score (p = 0.026), shorter CRPC-FS (hazard ratio 1.9; p = 0.046) and higher AVPC frequency (p = 0.01). Our results confirm that a TSG_low signature is an adverse prognostic factor and is associated with AVPC development in patients with mHSPC treated with ADT + ARPI. Further prospective validation is needed to define specific therapeutic strategies for these patients. We looked at outcomes for patients with metastatic hormone-sensitive prostate cancer treated with hormone therapies. We found that patients with low expression of two out of three tumor suppressor genes (TP53, RB1, PTEN) had worse clinical outcomes and had aggressive variants of prostate cancer. Measuring the expression of these genes in early-stage prostate cancer could help in finding better treatments for these patients.

Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients’ clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.