Abstract
Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL). Some of these failures can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based expression microarray datasets obtained prior to therapy from patients with DLBCL. Among genes in the GSH family, glutathione peroxidase 1 (GPX1) had the most significant adverse effect on disease-specific overall survival (dOS) in the primary dataset (n = 130) (HR: 1.68; 95% CI: 1.26-2.22; P < .001). This effect remained statistically significant after controlling for biologic signature, LLMPP cell-of-origin signature, and IPI score, and was confirmed in the validation dataset (n = 39) (HR: 1.7; 95% CI: 1.05-2.8; P = .033). Recursive partitioning identified a group of patients with low-level expression of GPX1 and multidrug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (P < .001). Overall, our findings suggest an important association of oxidative-stress defense and drug elimination with treatment failure in DLBCL and identify GPX1 and ABCB1 as potentially powerful biomarkers of early failure and disease-specific survival.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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Biomarkers, Tumor / biosynthesis*
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Biomarkers, Tumor / genetics
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Databases, Genetic
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Disease-Free Survival
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Drug Resistance, Neoplasm / genetics
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic* / genetics
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Glutathione Peroxidase / biosynthesis
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Glutathione Peroxidase / genetics
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Glutathione Peroxidase GPX1
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Humans
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Lymphoma, B-Cell / drug therapy
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, B-Cell / mortality
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Lymphoma, Large B-Cell, Diffuse / drug therapy
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism*
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Lymphoma, Large B-Cell, Diffuse / mortality
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Membrane Transport Proteins / biosynthesis*
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Membrane Transport Proteins / genetics
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Oligonucleotide Array Sequence Analysis
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Organic Anion Transporters / biosynthesis*
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Organic Anion Transporters / genetics
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Predictive Value of Tests
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Survival Rate
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Biomarkers, Tumor
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Membrane Transport Proteins
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Organic Anion Transporters
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glutathione transporter
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Glutathione Peroxidase
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Glutathione Peroxidase GPX1
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GPX1 protein, human