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

Davide Rossi, Silvia Rasi, Alice Di Rocco, Alberto Fabbri, Francesco Forconi, Annunziata Gloghini, Alessio Bruscaggin, Silvia Franceschetti, Marco Fangazio, Lorenzo De Paoli, Riccardo Bruna, Daniela Capello, Annalisa Chiappella, Chiara Lobetti Bodoni, Manuela Giachelia, Maria Chiara Tisi, Enrico M. Pogliani, Francesco Lauria, Marco Ladetto, Stefan HohausMaurizio Martelli, Umberto Vitolo, Antonino Carbone, Robin Foá, Gianluca Gaidano

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2405-2413
Number of pages9
JournalBlood
Volume117
Issue number8
DOIs
Publication statusPublished - Feb 24 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Rossi, D., Rasi, S., Di Rocco, A., Fabbri, A., Forconi, F., Gloghini, A., Bruscaggin, A., Franceschetti, S., Fangazio, M., De Paoli, L., Bruna, R., Capello, D., Chiappella, A., Bodoni, C. L., Giachelia, M., Tisi, M. C., Pogliani, E. M., Lauria, F., Ladetto, M., ... Gaidano, G. (2011). The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma. Blood, 117(8), 2405-2413. https://doi.org/10.1182/blood-2010-07-296244