title: The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma.
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.
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine & CRIFF, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, Novara, Italy. rossidav@med.unipmn.it
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Alice
authors.initials: A
authors.lastname: Di Rocco
authors.forename: Alberto
authors.initials: A
authors.lastname: Fabbri
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.forename: Alessio
authors.initials: A
authors.lastname: Bruscaggin
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: De Paoli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bruna
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiappella
authors.forename: Chiara
authors.initials: C
authors.lastname: Lobetti Bodoni
authors.forename: Manuela
authors.initials: M
authors.lastname: Giachelia
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Tisi
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Pogliani
authors.forename: Francesco
authors.initials: F
authors.lastname: Lauria
authors.forename: Marco
authors.initials: M
authors.lastname: Ladetto
authors.forename: Stefan
authors.initials: S
authors.lastname: Hohaus
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martelli
authors.forename: Umberto
authors.initials: U
authors.lastname: Vitolo
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001185:Artificial Intelligence; D003520:Cyclophosphamide / Q000627:therapeutic use; D004260:DNA Repair / Q000235:genetics*; D004317:Doxorubicin / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality*; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D017671:Platinum Compounds; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D018570:Risk Assessment; D015996:Survival Rate; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D017671:Platinum Compounds; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000070957:MutL Protein Homolog 1; D011241:Prednisone