Comparative analysis of deeply phenotyped GBM cohorts of 'short-term' and 'long-term' survivors.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). METHODS: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. RESULTS: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. CONCLUSION: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM.

Primary adenocarcinoma of the urinary bladder: value of cell cycle biomarkers.

Primary adenocarcinomas of the urinary bladder are uncommon, and the molecular pathways are currently not well defined. In this study, we assessed the association between biologic markers and clinicopathologic characteristics in a cohort of 21 patients with primary urinary bladder adenocarcinoma. Immunohistochemical staining for cell cycle-specific markers, including p53, p21, p27, Ki-67, and cyclin E, were performed on sections of a tissue microarray construct. The tumors were high grade in 12 (57%) and pT2 or higher in 18 (86%); lymph nodes were involved in 6 cases (29%); and there was pathologic evidence of schistosomiasis in 14 (67%). The best prognostic combination of markers was combined alterations in p27 and Ki-67 and was associated with stage (P = .012), grade (P = .005), DNA ploidy (P = .005), and lymph node involvement (P = .04). Stage, lymph node involvement, combined alterations of p27 and Ki-67, and combined alterations of all 5 biomarkers were associated with increased probability of disease recurrence and cancer-specific mortality (P < .05).

Expression of cell cycle-related molecular markers in patients treated with radical cystectomy for squamous cell carcinoma of the bladder.

We evaluated the association of p53, p21, p27, cyclin E, and Ki-67 expression with pathologic features and clinical outcomes of patients with squamous cell carcinoma (SCC) of the urinary bladder. Immunohistochemical staining was performed on radical cystectomy specimens with pure SCC from 1997 to 2003. Bright field microscopy imaging coupled with advanced color detection software was used. The relationship between these markers and pathologic parameters as well as clinical outcome was assessed. The study included 152 patients (80.9% with bilharziasis), 99 males and 53 females, with a median age of 51 years (range, 36-74 years). The presenting stage was T2 or higher, and the presenting grade was grade II or lower in 93.4% of patients. Altered cyclin E expression was associated with stages (P = .02), altered p21 with grades (P = .02), and altered p27 with lymphovascular invasion (P = .01). In multivariable analyses, altered p53 expression was the only marker associated with an increased risk of disease recurrence (hazards ratio, 1.77; 95% confidence interval, 1.03-3.38, P = .04; and hazards ratio, 2.28; 95% confidence interval, 1.01-5.70, P = .05) and bladder cancer-specific mortality (hazards ratio, 1.76; 95% confidence interval, 1.06-2.99, P = .05, and hazards ratio, 2.64; 95% confidence interval, 1.05-5.54, P = .05) in all patients and in patients with T1-3N0 tumors, respectively. In conclusion, cell cycle-related molecular markers are commonly altered in SCC of the urinary bladder. Only p53 had a prognostic role in patients treated with radical cystectomy for SCC. Our findings support the need for further evaluation of molecular markers and their signaling pathways in SCC.