G Protein as Subunit T393C Polymorphism Is Associated with Progression-Free Survival in Chronic Lymphocytic Leukemia.

Heterotrimeric G proteins mediate intracellular transduction of many hormone-receptor interactions. Activation of the G protein αs subunit (Gαs) upon stimulation of specific G Protein coupled receptors results in increased levels of the second messenger cAMP which has been shown to induce apoptosis in B-cells. On this background we investigated a potential association of a common silent single-nucleotid polymorphism (T393C) in the gene GNAS1 on chromosome 20 encoding Gαs with disease progression in patients with chronic lymphocytic leukemia (CLL). We genotyped the DNA from 109 patients with CLL and 100 healthy controls using PCR amplification followed by restriction analysis. Comparing the CLL patients with healthy controls we found no significant differences in allele frequencies or genotype distributions (CLL patients: 393CC 34 vs CT 51 vs TT 24; healthy controls: 393CC 25 vs CT 50 vs TT 25). However, progression-free survival (PFS) was significantly shorter in 393CC patients compared to T393 allele carriers (median PFS CC: 36 months; T-allele: median PFS not reached; log rank test: p=0.029; adjusted for Binet stage) after 5 years observation time. In multivariate analysis the T393C polymorphism was an independent prognostic factor for PFS. Our data suggest that the GNAS1 T393C polymorphism is not associated with the risk for B-CLL. However, the T393C polymorphism may be a prognostic marker for PFS. It is hypothesized that the 393T-allele is associated with increased cAMP concentrations and, therefore, with higher rates of apoptosis. Further studies assessing differences in the signaling pathway dependent on genotype are underway.