title: Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma.
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.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. babis.andreadis@uphs.upenn.edu
authors.forename: Charalambos
authors.initials: C
authors.lastname: Andreadis
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Peter
authors.initials: P
authors.lastname: Wahl
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.forename: Jane
authors.initials: J
authors.lastname: Houldsworth
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D030541:Databases, Genetic; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D027361:Organic Anion Transporters / Q000096:biosynthesis* / Q000235:genetics; D011237:Predictive Value of Tests; D015996:Survival Rate; D000094765:Glutathione Peroxidase GPX1
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014408:Biomarkers, Tumor; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C086860:glutathione transporter; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human