Dataset Information

The Association of GSTT1, GSTM1, and TNF-? Polymorphisms With the Risk and Outcome in Multiple Myeloma.

ABSTRACT: Oxidative stress and systemic inflammation are closely linked with increased risk of cancer development. Tumor necrosis factor alpha (TNF-?) 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-? 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-?). 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.

SUBMITTER: Zmorzynski S

PROVIDER: S-EPMC6798955 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Association of <i>GSTT1, GSTM1</i>, and <i>TNF-</i>α Polymorphisms With the Risk and Outcome in Multiple Myeloma.

Zmorzyński Szymon S Popek-Marciniec Sylwia S Szudy-Szczyrek Aneta A Wojcierowska-Litwin Magdalena M Korszeń-Pilecka Iwona I Chocholska Sylwia S Styk Wojciech W Hus Marek M Filip Agata A AA

Frontiers in oncology 20191011

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 prolife ...[more]

PMID: 31681592

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Project description:Background: Fourteen meta-analyses reported the individual effects of the GSTM1 and GSTT1 polymorphisms on leukemia risk. However, over 40 studies were not included in previously published meta-analyses. Moreover, one key aspect was that previous meta-analyses did not conduct the false-positive test on the aforementioned issues. Furthermore, previous meta-analyses did not observe the combined effects of GSTM1 present/null and GSTT1 present/null polymorphism with leukemia risk. Therefore, we conducted the current study to further analyze these associations. Objectives: This study aimed to investigate the association between the individual and combined effects of the GSTM1 present/null and GSTT1 present/null polymorphisms and the risk of leukemia. Methods: A meta-analysis was performed applying Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Moreover, false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to investigate the false-positive results. Results: The individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with a significantly increased leukemia risk in overall and several subgroup analyses, such as Asians, Caucasians, and so on. Then, further analysis was conducted using FPRP and BFDP. Significant associations were considered as “positive” results on the GSTM1 null genotype with leukemia risk in overall populations (FPRP < 0.001 and BFDP = 0.006), Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002). For the GSTT1 null genotype, significant associations were regarded “positive” results in overall populations, acute myeloid leukemia (AML), Asians, and East Asian population. For the combined effects of the GSTM1 and GSTT1 polymorphisms, significant associations were also considered “positive” results in the overall analysis of Asians, Indians, and East Asian population. Conclusion: This study strongly indicates that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians.

Dataset Information

The Association of GSTT1, GSTM1, and TNF-? Polymorphisms With the Risk and Outcome in Multiple Myeloma.

Publications

The Association of <i>GSTT1, GSTM1</i>, and <i>TNF-</i>α Polymorphisms With the Risk and Outcome in Multiple Myeloma.

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