The GNAS1 T393C polymorphism is associated with disease progression and survival in chronic lymphocytic leukemia.
OBJECTIVE
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of monoclonal mature B cells. The G protein Galphas subunit has been linked to proapoptotic processes in cancer cell lines. The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in different solid cancers.


METHODS
We retrospectively genotyped 144 patients with B-CLL to examine a potential association between T393C genotypes with progression-free survival (time from diagnosis to initiation of chemotherapy) and overall survival.


RESULTS
The C-allele frequency in the patient group was 0.57 and not significantly different from that of healthy blood donors. Median progression-free survival was significantly different between genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066). Multivariable analysis showed that besides of ZAP-70 (P = 0.005) and Binet stage (P < 0.001), the T393C polymorphism was an independent prognostic factor for progression-free survival [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. In Binet A stages, ZAP-70-positive patients with CC genotypes had a HR of 4.4 to receive first therapy compared with ZAP-70-negative patients with T-alleles (P = 0.0001). Regarding overall survival, CC genotypes (median overall survival, 197 months) were at highest risk for death compared with T-alleles (median overall survival, 310 months) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002).


CONCLUSIONS
Here, we show that the GNAS1 T393C status is a novel independent prognostic marker in patients with B-CLL. These results could help to define patients who could benefit from an early individualized therapy.
Frey
Ulrich H
UH
Institut für Pharmakogenetik, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Ulrich.Frey@uni-essen.de
Nückel
Holger
H
Sellmann
Ludger
L
Siemer
Dörte
D
Küppers
Ralf
R
Dürig
Jan
J
Dührsen
Ulrich
U
Siffert
Winfried
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002864:Chromogranins; D018450:Disease Progression; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs