Η σημασία των πολυμορφισμών των τρανσφερασών της γλουταθειόνης - S και των Fcγ υποδοχέων σε ασθενείς με μη-Hodgkin λεμφώματα

Abstract

DLBCL is the most common lymphoid neoplasm, accounting for ~30% of all non-Hodgkin lymphomas. The R-CHOP regimen has significantly improved the outcome of all subgroups of patients. However, a considerable proportion of patients still relapse and die of their disease. Genetic polymorphisms that are relevant to the mechanism of rituximab and CHOP are of great interest and may contribute to the variability in the outcomes.FcγRIIIa polymorphisms have been associated with response to single-agent rituximab in patients with follicular lymphoma and Wandelstrom macroglobulinemia GSTs polymorphisms have been associated both with favorable and unfavorable outcomes in a variety of cancer types. In Korean DLBCL patients they have been associated with chemotherapy related toxicities. We evaluated the prognostic impact of polymorphisms of the FcγRIIIa, GSTT1, GSTM1 and GSTP1 genes on the outcome of patients with DLBCL treated with R-CHOP. 28 (26%) were carriers of FcγRIIIa-158V/V, 23 (21%) of F/F and 58 (53%) of V/F. With respect to GST polymorphisms, 45 patients (52%) were GSTM1-null, 22 (25%) were GSTT1-null, 10 patients (11%) were GSTP1-105V/V, 42 (47%) were Ile/Ile and 38 (42%) were heterozygous. Eleven patients (13%) were GSTM1/GSTT1-double null, while 45 (52%) had only one deleted gene and 31 (36%) had no deletions. There were no significant associations between FcγRIIIa or GST genotypes and patients’ characteristics. Presence of GSTM1-null genotype was not associated with concomitant presence of GSTT1-null genotype (p=0.85), neither was presence of GSTP1-105V/V associated with concomitant presence of GSTM1/GSTT1-double null genotype (p=0.77). The 5-year EFS was 76% for FcγRIIIa-158V/V, 70% for V/F and 64% for F/F (p=0.68). For the GSTP1-105I/V polymorphism, 5-year EFS was 86% for V/V, 67% for V/I and 74% for I/I (p=0.58). The 5-year EFS was 72% for GSTM1-null patients versus 69% for GSTM1+ (p=0.66) and 77% for GSTT1-null versus 69% for GSTT1+ (p=0.47). Finally, 5-year EFS was 90% for GSTM1/GSTT1-double null patients versus 68% for patients with one deleted gene and 71% for patients with no deletions (p=0.59). Given that patients with GSTP1-105V/V genotype and patients with GSTM1/GSTT1-double null genotype had the highest EFS rates (86±13% and 90±9% respectively), further evaluation showed that presence of either GSTM1/GSTT1-double null genotype or GSTP1-105V/V genotype, was associated with a marginal improvement in EFS compared to any other genotype (p=0.13). Our data indicate that there is no individual effect of GSTs polymorphisms on EFS of DLBCL patients treated with R-CHOP. However, carriage of either GSTP1-105V/V polymorphism or GSTM1/GSTT1-double null genotype is present in 20% of patients and is slightly associated with improved EFS. This finding needs confirmation in a larger group of patients.