Several drugs used 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 2 independent cohorts of DLBCL treated with R-CHOP21 (training cohort, 163 cases; validation cohort, 145 cases). Among 35 single nucleotide polymorphisms analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival. DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (hazard ratio [HR] = 3.23; P < .001; q = 0.009) compared with patients carrying the AA genotype. Multivariate analysis adjusted for International Prognostic Index identified MLH1 AG/GG as an independent OS predictor (P < .001). The poor prognosis of MLH1 AG/GG was the result of 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, which are a mainstay of DLBCL first-and second-line treatment. (Blood. 2011;117(8):2405-2413)

The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma / D., Rossi; S., Rasi; DI ROCCO, Alice; A., Fabbri; F., Forconi; A., Gloghini; A., Bruscaggin; S., Franceschetti; M., Fangazio; L., De Paoli; R., Bruna; D., Capello; A., Chiappella; C., Lobetti Bodoni; M., Giachelia; M. c., Tisi; E. m., Pogliani; F., Lauria; M., Ladetto; S., Hohaus; Martelli, Maurizio; U., Vitolo; A., Carbone; Foa, Roberto; G., Gaidano. - In: BLOOD. - ISSN 0006-4971. - 117:8(2011), pp. 2405-2413. [10.1182/blood-2010-07-296244]

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

DI ROCCO, Alice;MARTELLI, Maurizio;FOA, Roberto;
2011

Abstract

Several drugs used 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 2 independent cohorts of DLBCL treated with R-CHOP21 (training cohort, 163 cases; validation cohort, 145 cases). Among 35 single nucleotide polymorphisms analyzed in the training series, MLH1 rs1799977 was the sole predicting overall survival. DLBCL carrying the MLH1 AG/GG genotype displayed an increased death risk (hazard ratio [HR] = 3.23; P < .001; q = 0.009) compared with patients carrying the AA genotype. Multivariate analysis adjusted for International Prognostic Index identified MLH1 AG/GG as an independent OS predictor (P < .001). The poor prognosis of MLH1 AG/GG was the result of 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, which are a mainstay of DLBCL first-and second-line treatment. (Blood. 2011;117(8):2405-2413)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/379706
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