Characterization of intron-1 haplotypes of the G protein β4 subunit gene – association with survival and progression in patients with urothelial bladder carcinoma

Authors:
  • KSKurt W. Schmid
    Kurt W. Schmid
  • WSWinfried Siffert
    Winfried Siffert
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Abstract
Purpose Polymorphisms in genes encoding subunits of heterotrimeric G proteins have been repeatedly associated with various cancers. As Gβγ signaling is presumed to be involved in proliferation and invasion processes, we analyzed genetic variations in regulatory regions of GNB4, which encodes the Gβ4 subunit, for their potential influence on cancer progression. Experimental Design We characterized the promoter of GNB4 and screened the promoter as well as exon 1 and intron 1 for single nucleotide polymorphisms by sequencing 100 healthy controls. Following a haplotype analysis, we determined the functional impact upon gene expression of the defined haplotypes by reporter assays, electrophoretic mobility shift assay and western blot. In addition, these haplotypes were tested for their relation to the disease course of urothelial bladder cancer. Results Whereas the promoter of GNB4 revealed no polymorphisms, 33 single nucleotide polymorphisms located in exon 1 and intron 1 were identified and together with a common exon-4 polymorphism implemented in haplotype analysis, which resulted in the determination of distinct haplotype blocks. Reporter activity was haplotype-dependently different (P=0.001). 1*1/1*1 showed increased Gβ4 protein (P=0.003), and bladder cancer patients carrying this diplotype displayed more progressive disease (P=0.046) and a significantly increased mortality (P=0.046). In multivariate analysis,the diplotypes were independent prognostic factors for survival and progression. Conclusion Intron-1 haplotypes of GNB4 may, thus, serve as predictive markers for progression and survival of patients suffering from bladder cancer.

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