Submitted September 15, 2006
Accepted December 9, 2006
Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma
Charalambos Andreadis*, Phyllis A Gimotty, Peter Wahl, Rachel Hammond, Jane Houldsworth, Stephen J Schuster, and Timothy R Rebbeck
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, United States
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
* Corresponding author; email: babis.andreadis{at}uphs.upenn.edu.
Standard chemotherapy fails in 40-50% 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 two 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 <0.001). This effect remained statistically significant after controlling for biological 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=0.033). Recursive partitioning identified a group of patients with low-level expression of GPx1 and multi-drug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (p<0.001). 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.
