Copy number profile of 24 oncogenes to identify putative recurrence-predictive markers in non muscle invasive bladder cancer

Objective

Patients with non muscle invasive bladder cancer (NMIBC) generally have an high risk to relapse locally after primary tumor resection. The search for new predictive markers of local recurrence represents an important goal for the management of this disease.
The urothelial cancer is an heterogeneous disease, and many studies regarding epigenetic, gene expression and genomic profiles have demonstrated the possibility to identify different molecular subtypes, with consequent different clinical behaviors.
In our study we evaluated the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR, BRAF) using an MLPA (Multiplex Ligation Probe Amplification) technique, aiming to verify their role as recurrence predictive markers.

Methods and results

BB2 were frequently gained in the overall case series Formaldehyde fixed paraffin-embedded tissues were recruited from 43 patients who underwent transurethral resection of the bladder (TURB) at the Department of Urology of Morgagni-Pierantoni Hospital in Forlì between 1997 and 2006. On the basis of 2004 World Health Organization criteria, final diagnosis was low grade non muscle invasive bladder cancer (NMIBC) in 28 patients and high grade NMIBC in 13 patients. At a median follow up of 5 years 20 patients were still disease-free and 23 had experienced one or more episodes of local recurrence.
Amplification frequencies were analyzed for all the genes in the two subgroups of patients.
Many genes such as MDM4, MET, CDK4, MYC, TOP2A, AURKA, ER (frequencies ranging from 0.46 to 0.21).
Only MDM4 amplification was able to identify recurrence risk, resulting significantly higher in non recurrent patients with the respect to recurrent ones (0.65 vs 0.3; Fisher test p=0.0234). The recurrence free survival analysis confirmed the recurrence-predictive role of this gene (Log-Rank test p= 0.0409).

Discussion

Our primary objective was to verify any possible association between copy number variations of selected genes and the risk of local recurrence in NMIBC. However, among the 24 analyzed genes, we found only a statistical association with MDM4. We observed some other important frequently amplified genes in the overall case series (MET,MYC, TOP2A, AURKA, ERBB2, MDM2,CCND1, BRAF) and our findings are in agreement with the literature data obtained on gene copy number alterations in bladder cancer.
The possibility to have predictive markers of recurrence represents a goal for bladder cancer patients management and compliance.
Our results pave the way for further prospective, validation studies on larger cohorts of patients

References

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