Abstract
Oxidative stress and systemic inflammation are closely linked with increased risk of cancer development. Tumor necrosis factor alpha (TNF-α) is one of the pro-inflammatory cytokines. Glutathione S-transferases (GSTs) are enzymes involved in oxidative stress handling. Polymorphisms of genes encoding mentioned molecules may potentially influence the risk and the outcome in neoplastic diseases. Multiple myeloma (MM) is a hematological malignancy characterized by clonal, atypical plasma cell proliferation. In the present study we investigated the association of deletion polymorphisms in GSTT1/GSTM1 genes and single nucleotide polymorphisms (SNPs) in the TNF-α gene at positions −308/−238 with the risk and outcome in MM and sensitivity to bortezomib under in vitro conditions. One hundred newly diagnosed MM patients and 100 healthy blood donors were genotyped by means of multiplex PCR (for GSTs) and PCR-RFLP (for TNF-α). In a subgroup of 50 MM patients, bone marrow cells were treated with bortezomib in vitro. Patients with −238GA+AA or GSTT1-null genotypes had 2.0 (p = 0.002) or 2.29 (p = 0.013) fold increased risk of MM. The interaction effects and risk of MM were observed in GSTT1/GSTM1-null (OR = 2.82, p = 0.018), −308/−238GA+AA (OR = 5.63, p < 0.001), as well as in all combinations of −308 with GSTs. The −308/−238GA+AA genotypes in comparison to GG were associated with earlier MM onset−61.14 vs. 66.86 years (p = 0.009) and 61.72 vs. 66.52 years (p = 0.035), respectively. Patients with GSTM1-present had shorter progression-free-survival (15.17 vs. 26.81 months, p = 0.003) and overall-survival (22.79 vs. 34.81 months, p = 0.039) compared with GSTM1-null. We did not observe relationship between response rate and studied polymorphisms. The in vitro study revealed significantly higher number of apoptotic cells at 12 nM of bortezomib in GSTT1-present, GSTM1-null/present, −308GG and −238GG/GA+AA genotypes. Our findings comprise large analysis of studied polymorphisms in MM.
Highlights
Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow [1]
GSTs play a critical role in protecting DNA and cell structures against the reactive oxygen species (ROS) [6]
Increased production of ROS leads to the accumulation of DNA mutations and activates a positive feedback loop via TNF-α, which promotes the synthesis of inflammatory cytokines
Summary
Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow [1]. GSTs are involved in the elimination of several chemical carcinogens and protect cellular DNA against ROS-induced damage. This enables genomic maintenance [7]. The ability to metabolize carcinogens varies between individuals These differences depend on polymorphisms of genes coding GST theta-1 and GST mu-1 enzymes – GSTT1 (locus 22q11.2) and GSTM1 (locus 1p13.3), respectively [4, 6]. The polymorphisms of GSTT1 and GSTM1 genes are present in the form of null genotypes, which are caused by deletion of both alleles at a single locus. GSTM1 null polymorphism means that all exons (count = 6) and introns are removed (6 kbp deletion), but promoter and other non-coding regions (5′UTR, 3′UTR) are present. Null genotype results in a complete lack of corresponding enzyme activity [8]
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