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

• Published in: Blood Vol. 117; no. 8; pp. 2405 - 2413
• Main Authors: Rossi, Davide, Rasi, Silvia, Di Rocco, Alice, Fabbri, Alberto, Forconi, Francesco, Gloghini, Annunziata, Bruscaggin, Alessio, Franceschetti, Silvia, Fangazio, Marco, De Paoli, Lorenzo, Bruna, Riccardo, Capello, Daniela, Chiappella, Annalisa, Lobetti Bodoni, Chiara, Giachelia, Manuela, Tisi, Maria Chiara, Pogliani, Enrico M., Lauria, Francesco, Ladetto, Marco, Hohaus, Stefan, Martelli, Maurizio, Vitolo, Umberto, Carbone, Antonino, Foà, Robin, Gaidano, Gianluca
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 24.02.2011; Americain Society of Hematology
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Artificial Intelligence; Biological and medical sciences; Cyclophosphamide - therapeutic use; DNA Repair - genetics; Doxorubicin - therapeutic use; Genotype; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - mortality; Medical sciences; MutL Protein Homolog 1; Nuclear Proteins - genetics; Pharmacogenetics - methods; Platinum Compounds; Polymorphism, Single Nucleotide; Precision Medicine; Predictive Value of Tests; Prednisone - therapeutic use; Prognosis; Risk Assessment; Survival Rate; Vincristine - therapeutic use; Hematology; B cell neoplasm; Malignant hemopathy; Non Hodgkin lymphoma; Survival; DNA repair; Mechanism; Lymphoproliferative syndrome; DNA; Genetics; Diffuse large B cell lymphoma; Predictive factor; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-07-296244

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.