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


METHODS
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.


CONCLUSIONS
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.
Frey
Ulrich H
UH
Institut für Pharmakogenetik, Universitätsklinikum Essen, Germany. Ulrich.Frey@uni-essen.de
Lümmen
Gerd
G
Jäger
Tobias
T
Jöckel
Karl-Heinz
KH
Schmid
Kurt W
KW
Rübben
Herbert
H
Müller
Norbert
N
Siffert
Winfried
W
Eisenhardt
Andreas
A
D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D002864:Chromogranins; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy / Q000379:methods; D011110:Polymorphism, Genetic; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs