The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma

Several drugs utilized for diffuse large B-cell lymphoma (DLBCL) treatment rely on DNA damage for tumor cell killing. We verified the prognostic impact of the host DNA repair genotype in two independent cohorts of DLBCL treated with R-CHOP21 (training cohort: 163 cases; validation cohort: 145 cases). Among 35 SNPs analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival (OS). DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (HR:3.23; p<.001; q=.009) compared to patients carrying the AA genotype. Multivariate analysis adjusted for IPI identified MLH1 AG/GG as an independent OS predictor (p<.001). The poor prognosis of MLH1 AG/GG was due to an increased risk of failing both R-CHOP21 (HR: 2.02; p=.007) and platinum-based second line (HR: 2.26; p=.044) treatment. Survival analysis in the validation series confirmed all outcomes predicted by MLH1 rs1799977. The effect on OS of MLH1, a component of the DNA mismatch repair system, is consistent with its role in regulating the genotoxic effects of doxorubicin and platinum compounds, that are a mainstay of DLBCL first and second line treatment.