DNA Repair Gene, XRCC1 Polymorphisms Are Associated with Chemotherapy Induced Toxicity in Patients with Diffuse Large B Cell Lymphoma Who Received Frontline R-CHOP Chemotherapy.

Abstract

BACKGROUND. X-ray repair cross-complementing group I (XRCC1) is a DNA repair gene. Polymorphisms in DNA repair genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of three polymorphisms in XRCC1 codon 194 (Arg to Trp), 280 (Arg to His), and 399 (Arg to Gln), with grade 3 or 4 toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy in 145 patients with diffuse large B cell lymphoma (DLBCL).METHODS. A total of 145 patients who received R-CHOP chemotherapy as a frontline regimen DLBCL were included in this retrospective study from 3 hospitals in Korea. The genotypes of XRCC1 at the Arg194Trp, Arg280His, and Arg399Gln were determined by direct sequencing methods. The clinical characteristics, treatment outcomes and grade 3 and 4 toxicities of the patients were compared using Chi-square, Fisher exact, Mann-Whitney U tests, or logistic regression according to the XRCC1 polymorphisms.RESULTS. Carrying at least one variant XRCC1 Arg194Trp alleles (194Arg/Trp or 194Trp/Trp) and XRCC1 Arg399Gln variant alleles (399Arg/Gln or 399Gln/Gln) was associated with a significantly increased risk of grade 3 or 4 gastrointestinal toxicity (Arg194Trp alleles; odds ratio, 3.489; 95% confidence interval, 0.126–1.568; P=0.001, Arg399Gln alleles; odds ratio, 2.577; 95% confidence interval, 0.144–1.096; P=0.011, respectively). The carriers of XRCC1 Arg280His variant alleles (280Arg/His or 280His/His) was associated with grade 3 or 4 neutropenia (odds ratio, 2.047; 95% confidence interval, 0.008–0.450; P=0.043). No differences in the patient characteristics, disease characteristics, response, and survival in patients with DLBCL who received frontline R-CHOP chemotherapy were observed according to three XRCC1 polymorphims.CONCLUSIONS. This study demonstrates that the patients carrying at least one variant XRCC1 Arg194Trp or XRCC1 Arg399Gln alleles have a 2.5-to 3.5-fold increased risk of grade 3 or 4 gastrointestinal toxicity and the patients carrying at least one variant XRCC1 Arg280His allele have a 2.0-fold increased risk of grade 3 or 4 neutropenia when treated with frontline R-CHOP chemotherapy and this has implications for optimizing treatment with such agents.