TY - JOUR
T1 - The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma
AU - Rossi, Davide
AU - Rasi, Silvia
AU - Di Rocco, Alice
AU - Fabbri, Alberto
AU - Forconi, Francesco
AU - Gloghini, Annunziata
AU - Bruscaggin, Alessio
AU - Franceschetti, Silvia
AU - Fangazio, Marco
AU - De Paoli, Lorenzo
AU - Bruna, Riccardo
AU - Capello, Daniela
AU - Chiappella, Annalisa
AU - Bodoni, Chiara Lobetti
AU - Giachelia, Manuela
AU - Tisi, Maria Chiara
AU - Pogliani, Enrico M.
AU - Lauria, Francesco
AU - Ladetto, Marco
AU - Hohaus, Stefan
AU - Martelli, Maurizio
AU - Vitolo, Umberto
AU - Carbone, Antonino
AU - Foá, Robin
AU - Gaidano, Gianluca
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Non-Hodgkin Lymphoma
KW - Polymorphism
KW - Non-Hodgkin Lymphoma
KW - Polymorphism
UR - http://hdl.handle.net/10807/6316
U2 - 10.1182/blood-2010-07-296244
DO - 10.1182/blood-2010-07-296244
M3 - Article
SN - 0006-4971
VL - 2011
SP - 2405
EP - 2413
JO - Blood
JF - Blood
ER -