The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.
The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s 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 G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.
Frey
Ulrich H
UH
Institut für Pharmakologie, Universitätsklinikum, Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Ulrich.Frey@uni-essen.de
Eisenhardt
Andreas
A
Lümmen
Gerd
G
Rübben
Herbert
H
Jöckel
Karl-Heinz
KH
Schmid
Kurt W
KW
Siffert
Winfried
W
D002295:Carcinoma, Transitional Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002864:Chromogranins; D018572:Disease-Free Survival; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D012907:Smoking / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs