Gain of Chromosome 12 Is an Adverse Prognostic Factor for Clinically Localized Clear Cell Renal Cell Carcinoma: A Chromogenic In-Situ Hybridization (CISH) Study.
Huiying He, Paul Elson, Hakan Aydin, Steve Campbell, Brian Rini, Cristina Magi-Galluzzi, Ray Tubbs, Ming Zhou. Cleveland Clinic; Peking University, Health Science Center, Beijing, China
Background: The role of tumor suppressor gene p53 and its major negative regulator MDM2 in clear cell renal cell carcinoma (CCRCC) has only been addressed recently. A few studies have generated conflicting data regarding MDM2 expression and its prognostic significance in CCRCC. This study examined the quantitative alteration of MDM2 gene and chromosome 12 and their correlation with clinical outcomes.
Design: Dual-color chromogenic in situ hybridization using probes for MDM2 (12q15) and centromeric region of chromosome 12 was performed on a tissue microarray containing 333 clinically localized CCRCC treated surgically between 1990 and 2003. The copy number of MDM2 gene and chromosome 12 was quantified under a bright field microscopy. An MDM2/chromosome 12 ratio >2.0 indicated amplified, and a ratio <2.0 indicated nonamplified MDM2 gene. Simultaneous Cases displaying >2 signals of both probes and the MDM2/chromosome 12 ratio <2.0 indicated the gain of chromosome 12. Results were correlated to the clinicopathological parameters, recurrence-free survival (RFS) and overall survival (OS).
Results: Gain of chromosome 12 was present in 22.5 % (75/333) clinically localized CCRCC. MDM2 amplification was only observed in 2.7% (9/333) cases. The gain of chromosome 12 was significantly associated with adverse pathological factors, including higher Fuhrman grade and pathological stage, and the presence of necrosis (all p<0.01), but not with age or sarcomatoid differentiation. Patients with chromosome 12 gains showed significantly worse 5-year RFS (64+6% vs 87+2%, p<0.0001) and OS (64+6% vs 85+2%, p<0.0001) in univariable models. In multivariable Cox models, chromosome 12 gain, pathologic stage, Fuhrman grade and necrosis all significantly correlated with RFS. The hazard ratio for chromosome 12 gain was 2.86 (p=0.002).
Conclusions: Isolated MDM2 gene amplification is rare in clinically localized CCRCC. However, gain of chromosome 12 is present in 22.5% of CCRCC and is an independent predictor for poor prognosis. Studies are ongoing to identify candidate genes on chromosome 12 that confer adverse prognosis.
Category: Genitourinary (including renal tumors)
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 116, Wednesday Morning