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The GNAS1 T393C Polymorphism Predicts Survival in Patients with Clear Cell Renal Cell Carcinoma

Authors' Affiliations: ¹ Institut für Pharmakogenetik; ² Urologische Klinik; ³ Institut für Medizinische Informatik, Biometrie und Epidemiologie; ⁴ Institut für Pathologie; and ⁵ Institut für Transfusionsmedizin, Universitätsklinikum Essen, Essen, Germany

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

Purpose: G proteins mediate signaling from cell surface receptors to specific intracellular proteins. In vitro cancer cell line studies revealed a link between the Gs protein and proapoptotic processes. We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Gs and a more favorable clinical course in bladder and colorectal cancer patients compared both with TC or CC genotypes.

Experimental Design: In the present study, 150 patients with clear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome.

Results: The C-allele frequency in the renal cell carcinoma patient group was 0.51, which is not significantly different from that of a healthy blood donor group. Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers.

Conclusion: Our results show that besides tumor stage, lymph node status, and tumor grade, the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker.

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