The G-Allele of the PSMA6-8C>G polymorphism is associated with poor outcome in multiple myeloma independently of circulating proteasome serum levels.
BACKGROUND
The proteasome system plays a crucial role in several malignant disorders, especially in multiple myeloma (MM). The G-allele of a single nucleotide polymorphism (SNP) -8C>G in the gene PSMA6, one of seven alpha-subunit genes of the 20S proteasome, was associated with myocardial infarction. Moreover, PSMA6 mRNA expression in human B-cell lines depended on genotypes. We investigated a potential role of this novel SNP in patients with MM.


METHODS
PSMA6 genotypes of 116 patients with MM were associated with survival. Circulating proteasome levels (CPL) dependent on -8C>G genotypes of 70 newly diagnosed patients were studied using an anti-20S proteasome enzyme-linked immunoabsorbant assay (ELISA).


RESULTS
Genotype distribution (69 CC, 44 CG, 3 GG) was compatible with Hardy-Weinberg equilibrium. Kaplan-Meier curves revealed a significant association of PSMA6-8C>G with 5-yr survival (P = 0.014). Median survival time was 43 months for the GG genotype and 50 months for the CG genotype. It was not reached within follow-up by the CC genotype (CC 5-yr survival rate 61.2%). Following hazard ratio (HR) for overall survival was calculated: G-allele vs. CC genotype: 2.038, 95% CI 1.14-3.65, P = 0.017. In multivariate analysis the G-allele was an independent prognostic factor (HR 2.1, P = 0.014). CPL were not significantly different between genotypes [mean CPL: CC 284.9 ng/mL vs. 303.3 ng/mL G-allele carriers (P = 0.709)].


CONCLUSIONS
These results suggest the G-allele of the PSMA6-8C>G polymorphism as a possible survival prognosticator.
Bachmann
Hagen S
HS
Institute of Pharmacogenetics, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany. hagen.bachmann@uk-essen.de
Novotny
Jürgen
J
Sixt
Stephan
S
Liebisch
Peter
P
Frey
Ulrich H
UH
Dührsen
Ulrich
U
Siffert
Winfried
W
Nückel
Holger
H
D000368:Aged; D000483:Alleles; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009203:Myocardial Infarction; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D015996:Survival Rate
C465641:PSMA6 protein, human; D046988:Proteasome Endopeptidase Complex