GNAS1 T393C polymorphism and survival in patients with sporadic colorectal cancer.
OBJECTIVE
Signaling via the G protein Galpha s pathway is linked to proapoptotic processes in cancer cell lines. We have recently shown an association between the GNAS1 T393C polymorphism and disease progression in patients with bladder cancer with homozygous TT genotypes displaying increased transcription of Galpha s and a more favorable clinical course compared with C-allele carriers.


METHODS
In the present study, 151 patients with sporadic colorectal cancer were retrospectively genotyped to examine a potential association between T393C genotypes and survival. Moreover, two other single-nucleotide polymorphisms in common haplotype blocks within the gene GNAS1 and their interaction with the T393C polymorphism were investigated.


RESULTS
The allele frequency in the patients group was not significantly different from that of healthy blood donors. Kaplan-Meier curves for overall survival (mean follow-up, 43 months) showed that in International Union Against Cancer (UICC) stages I to II, the 5-year survival rate was significantly higher in TT genotypes (87.8%) compared with TC (71.0%) and CC genotypes (50.0%; P = 0.009), whereas no genotype effect could be observed for UICC stages III to IV. In multivariate Cox proportional analysis the T393C polymorphism was an independent prognostic factor for survival. Homozygous CC patients were at highest risk for death (hazard ratio, 12.1; P = 0.006) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. The two haplotype blocks investigated were not associated with clinical outcome.


CONCLUSIONS
The results support the role of the T393C polymorphism as a marker for survival in patients with colorectal cancer stages I to II and in the identification of patients who may benefit from adjuvant chemotherapy.
Frey
Ulrich H
UH
Institute of Pharmacology, University Hospital of Essen, Essen, Germany. Ulrich.Frey@uni-essen.de
Alakus
Hakan
H
Wohlschlaeger
Jeremias
J
Schmitz
Klaus J
KJ
Winde
Günther
G
van Calker
Hans G
HG
Jöckel
Karl-Heinz
KH
Siffert
Winfried
W
Schmid
Kurt W
KW
D000368:Aged; D017209:Apoptosis; D002864:Chromogranins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis
D002864:Chromogranins; D005819:Genetic Markers; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs