AUTHOR=Zmorzyński Szymon , Popek-Marciniec Sylwia , Szudy-Szczyrek Aneta , Wojcierowska-Litwin Magdalena , Korszeń-Pilecka Iwona , Chocholska Sylwia , Styk Wojciech , Hus Marek , Filip Agata A. 

TITLE=The Association of GSTT1, GSTM1, and TNF-α Polymorphisms With the Risk and Outcome in Multiple Myeloma

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.01056

DOI=10.3389/fonc.2019.01056

ISSN=2234-943X

ABSTRACT=<p>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 <italic>GSTT1/GSTM1</italic> genes and single nucleotide polymorphisms (SNPs) in the <italic>TNF-</italic>α gene at positions −308/−238 with the risk and outcome in MM and sensitivity to bortezomib under <italic>in vitro</italic> 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 <italic>in vitro</italic>. Patients with −238GA+AA or <italic>GSTT1</italic>-null genotypes had 2.0 (<italic>p</italic> = 0.002) or 2.29 (<italic>p</italic> = 0.013) fold increased risk of MM. The interaction effects and risk of MM were observed in <italic>GSTT1/GSTM1</italic>-null (OR = 2.82, <italic>p</italic> = 0.018), −308/−238GA+AA (OR = 5.63, <italic>p</italic> &lt; 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 (<italic>p</italic> = 0.009) and 61.72 vs. 66.52 years (<italic>p</italic> = 0.035), respectively. Patients with <italic>GSTM1</italic>-present had shorter progression-free-survival (15.17 vs. 26.81 months, <italic>p</italic> = 0.003) and overall-survival (22.79 vs. 34.81 months, <italic>p</italic> = 0.039) compared with <italic>GSTM1</italic>-null. We did not observe relationship between response rate and studied polymorphisms. The <italic>in vitro</italic> study revealed significantly higher number of apoptotic cells at 12 nM of bortezomib in <italic>GSTT1</italic>-present, <italic>GSTM1</italic>-null/present, −308GG and −238GG/GA+AA genotypes. Our findings comprise large analysis of studied polymorphisms in MM.</p>