%0 Journal Article %1 Hoffmann.2010 %A Hoffmann, Marion %A Schirmer, Markus A. %A Tzvetkov, Mladen V. %A Kreuz, Markus %A Ziepert, Marita %A Wojnowski, Leszek %A Kube, Dieter %A Pfreundschuh, Michael %A Trümper, Lorenz %A Loeffler, Markus %A Brockmöller, Jürgen %D 2010 %J Cancer research %K Adolescent Adult Antineoplastic_Combined_Chemotherapy_Protocols/administration_&_dosage/therapeutic_use Cyclophosphamide/administration_&_dosage Doxorubicin/administration_&_dosage Etoposide/administration_&_dosage Female Gene_Expression Humans Lymphoma,_Non-Hodgkin/drug_therapy/enzymology/genetics Male Middle_Aged NADPH_Oxidase/biosynthesis/genetics/metabolism Polymorphism,_Single_Nucleotide Prednisolone/administration_&_dosage Protein_Subunits RNA,_Messenger/biosynthesis/genetics Treatment_Outcome Vincristine/administration_&_dosage Young_Adult %N 6 %P 2328–2338 %T A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related to gene expression, enzyme activity, and outcome in non-Hodgkin lymphoma %V 70 %X NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A>G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A>G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A>G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 95\% confidence interval (95\% CI), 1.31-2.90; P = 0.001 compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04-2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30-2.26) and 1.59 (1.14-2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A>G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities.

@article{Hoffmann.2010, abstract = {NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A>G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A>G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A>G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 [95\% confidence interval (95\% CI), 1.31-2.90; P = 0.001] compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04-2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30-2.26) and 1.59 (1.14-2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A>G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities.}, added-at = {2014-10-14T15:28:03.000+0200}, author = {Hoffmann, Marion and Schirmer, Markus A. and Tzvetkov, Mladen V. and Kreuz, Markus and Ziepert, Marita and Wojnowski, Leszek and Kube, Dieter and Pfreundschuh, Michael and Trümper, Lorenz and Loeffler, Markus and Brockmöller, Jürgen}, biburl = {https://www.bibsonomy.org/bibtex/26c78db0723976e369f3a2cb4942023ab/drtester}, interhash = {ac493c21f6ff65917cd00f115a590f3e}, intrahash = {6c78db0723976e369f3a2cb4942023ab}, journal = {Cancer research}, keywords = {Adolescent Adult Antineoplastic_Combined_Chemotherapy_Protocols/administration_&_dosage/therapeutic_use Cyclophosphamide/administration_&_dosage Doxorubicin/administration_&_dosage Etoposide/administration_&_dosage Female Gene_Expression Humans Lymphoma,_Non-Hodgkin/drug_therapy/enzymology/genetics Male Middle_Aged NADPH_Oxidase/biosynthesis/genetics/metabolism Polymorphism,_Single_Nucleotide Prednisolone/administration_&_dosage Protein_Subunits RNA,_Messenger/biosynthesis/genetics Treatment_Outcome Vincristine/administration_&_dosage Young_Adult}, number = 6, pages = {2328–2338}, timestamp = {2014-10-14T15:28:03.000+0200}, title = {A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related to gene expression, enzyme activity, and outcome in non-Hodgkin lymphoma}, volume = 70, year = 2010 }