GNAS1 T393C polymorphism is associated with clinical course in patients with intrahepatic cholangiocarcinoma.
OBJECTIVE
The GNAS1 locus encodes the Galphas protein, which stimulates the formation of cyclo-adenosinemonophosphate (cAMP). The cAMP pathway mediates pleiotropic effects, including the regulation of apoptosis and proliferation. We have recently shown that TT genotypes of the single-nucleotide polymorphism T393C in the gene GNAS1 predict the clinical outcome of patients with various carcinomas.


METHODS
Eighty-seven patients with intrahepatic cholangiocarcinoma (ICC) were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome.


RESULTS
ICCs of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate. Homozygous TT patients were at highest risk for cancer-related deaths (hazard ratio = 2.74; 95% confidence interval = 1.03-7.28) compared with C-allele carriers. Kaplan-Meier curves for disease-specific overall and local recurrence-free survival in a subgroup with R(0)-resected ICC showed a significant association of T393 homozygosity with outcome, which was confirmed in multivariate Cox regression analysis.


CONCLUSIONS
GNAS1 T393C is a novel independent host factor for disease progression in patients with ICC. Our finding that TT homozygosity (and not CC homozygosity) was associated with unfavorable clinical outcome points to the complex and differing functional effects induced by GNAS1 T393C polymorphism in various human carcinomas.
Schmitz
Klaus J
KJ
Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
Lang
Hauke
H
Frey
Ulrich H
UH
Sotiropoulos
Georgios C
GC
Wohlschlaeger
Jeremias
J
Reis
Henning
H
Takeda
Atsushi
A
Siffert
Winfried
W
Schmid
Kurt W
KW
Baba
Hideo A
HA
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D000951:Antigens, Neoplasm / Q000032:analysis; D017209:Apoptosis / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000401:mortality; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D016022:Case-Control Studies; D002455:Cell Division / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000401:mortality; D002864:Chromogranins; D018572:Disease-Free Survival; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D002864:Chromogranins; D019394:Ki-67 Antigen; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs