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 Blood, 15 April 2007, Vol. 109, No. 8, pp. 3409-3416.
Prepublished online as a Blood First Edition Paper on December 21, 2006; DOI 10.1182/blood-2006-09-047621.

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NEOPLASIA

Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma

Charalambos Andreadis1,2, Phyllis A. Gimotty2, Peter Wahl2, Rachel Hammond2, Jane Houldsworth3, Stephen J. Schuster1, and Timothy R. Rebbeck2

1 Abramson Cancer Center and 2 Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania, Philadelphia, PA; 3 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY

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.


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