Predictive value of 9p21, CCND1, CMYC, and EGFR gains in non-muscle invasive bladder cancer

The clinical behaviour of superficial bladder tumours is characterized by recurrence, which directs their clinical management. Identification of the molecular alterations critical for tumour recurrence and progression would enable a better management of patients with bladder cancer. The aim of this study was to assess the association between alterations in gene dosage and clinical parameters in patients with non-muscle invasive bladder carcinoma. To achieve this goal, the CCND1, CMYC, and EGFR genes and the 9p21 locus were analyzed by fluorescence in situ hybridization and Cyclin D1, p53, p21, and p16 proteins by immunochemistry in a tissue microarray composed of 152 Ta-T1 bladder tumours. Loss of 9p21 correlated with a decrease or absence of p16 protein expression as well as with an increase of Cyclin D1 and p21 protein expression. High gain of EGFR associated with high polysomy of chromosome 7 predicted shorter recurrence-free survival in non-muscle invasive tumours (OR = 2.29, 95%CI = 1.33–3.95, P = 0.003), and in particular in TaG2 tumours (OR = 5.06, 95%CI = 1.35–19.01, P = 0.016). Grade predicted shorter recurrence-free survival in T1G2 tumours (OR = 3.31, 95%CI = 1.04–10.49, P = 0.042). High gain of 9p21 associated with polysomy of chromosome 9 and high gain of CMYC predicted shorter progression-free survival in T1 tumours (OR = 7.17, 95%CI = 1.73–34.66, P = 0.014 and OR = 7.48, 95%CI = 1.85–30.29 P = 0.005, respectively). High gain of 9p21 remained as a single independent prognostic factor for tumour progression in T1G3 tumours (OR = 8.21, 95%CI = 1.36–49.31, P = 0.021). Tumour grade and CCND1 amplification associated with poor tumour specific survival in non-muscle invasive bladder tumours (OR = 4.32, 95%CI = 1.18–15.80, P = 0.027 and OR = 3.63, 95%CI = 1.11–11.95, P = 0.034, respectively), but this association was not significant when the analysis was performed separately in Ta and T1 tumours. High gain of EGFR is the main prognostic factor of tumour recurrence in superficial bladder tumours. High gain of 9p21 could be a good predictor for tumour progression in non-muscle invasive tumours, but especially in T1G3 tumours.