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The T393C Polymorphism of the Gs Gene (GNAS1) Is a Novel Prognostic Marker in Bladder Cancer

¹ Institut für Pharmakologie, ² Urologische Klinik, ³ Institut für Medizinische Informatik, Biometrie und Epidemiologie and West German Tumor Centre, and ⁴ Institut für Pathologie, Universitätsklinikum, Essen, Germany

Requests for reprints: Ulrich H. Frey, Institut für Pharmakologie, Universitätsklinikum, Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Phone: 49-201-7233459; Fax: 49-201-7235968. E-mail: Ulrich.Frey{at}uni-essen.de

The G protein Gs pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding Gs as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that Gs mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential Gs mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of Gs in bladder cancer progression.

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