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

The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma
The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma
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.
0006-4971
2405-2413
Rossi, Davide
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Rasi, Silvia
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Di Rocco, Alice
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Fabbri, Alberto
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Forconi, Francesco
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Gloghini, Annunziata
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Bruscaggin, Alessio
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Franceschetti, Silvia
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Fangazio, Marco
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De Paoli, Lorenzo
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Bruna, Riccardo
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Capello, Daniela
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Chiappella, Annalisa
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Lobetti Bodoni, Chiara
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Giachelia, Manuela
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Tisi, Maria Chiara
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Pogliani, Enrico M.
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Lauria, Francesco
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Ladetto, Marco
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Hohaus, Stefan
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Martelli, Maurizio
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Vitolo, Umberto
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Carbone, Antonino
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Foà, Robin
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Gaidano, Gianluca
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Rossi, Davide
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Rasi, Silvia
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Di Rocco, Alice
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Fabbri, Alberto
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Forconi, Francesco
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Gloghini, Annunziata
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Bruscaggin, Alessio
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Franceschetti, Silvia
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Fangazio, Marco
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De Paoli, Lorenzo
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Bruna, Riccardo
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Capello, Daniela
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Chiappella, Annalisa
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Lobetti Bodoni, Chiara
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Giachelia, Manuela
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Tisi, Maria Chiara
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Pogliani, Enrico M.
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Lauria, Francesco
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Ladetto, Marco
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Hohaus, Stefan
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Martelli, Maurizio
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Vitolo, Umberto
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Carbone, Antonino
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Foà, Robin
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Gaidano, Gianluca
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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 and Gaidano, Gianluca (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. (doi:10.1182/blood-2010-07-296244). (PMID:21156845)

Record type: Article

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.

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More information

e-pub ahead of print date: 15 July 2010
Published date: 24 February 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 358132
URI: http://eprints.soton.ac.uk/id/eprint/358132
ISSN: 0006-4971
PURE UUID: 154e5f2b-97e4-4d45-85cd-088aa89e0848
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 08 Oct 2013 10:47
Last modified: 15 Mar 2024 03:40

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Contributors

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

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