Validation of single nucleotide polymorphisms potentially related to R-CHOP resistance in diffuse large B-cell lymphoma patients

Abstract

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 (VEGFA gene) and sex (P = 0.046), and rs1625895 (TP53 gene) and stage (P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 (NCF4 gene) and rs1800871 (IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.

Keywords: Diffuse large B-cell lymphoma (DLBCL); R-CHOP regimen; biomarkers; host genetics; single nucleotide polymorphism (SNP); tumor drug resistance.

Figure 1

PFS and OS of the whole case series according to NCF4 (additive model) and IL10 (dominant model) SNPs (Kaplan-Meier method, log-rank Mantel-Cox test). PFS: Progression-free survival; OS: overall survival; SNPs: single nucleotide polymorphisms.

Figure 2

PFS and OS of patients with R-IPI 1-2 according to NCF4 (additive model) and IL10 (dominant model) SNPs (Kaplan-Meier method, log-rank Mantel-Cox test). PFS: Progression-free survival; OS: overall survival; R-IPI: revised International Prognostic Index; SNPs: single nucleotide polymorphisms.