Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma

Pharmacogenomics. 2015;16(4):361-72. doi: 10.2217/pgs.14.179.

Abstract

Aim: To identify gene variants responsible for anthracycline-induced cardiotoxicity.

Patients & methods: Polymorphisms of the NADPH oxidase subunits and of the anthracycline transporters ABCC1, ABCC2 and SLC28A3 were genotyped in elderly patients (61-80 years) treated for aggressive CD20(+) B-cell lymphomas with CHOP-14 with or without rituximab and followed up for 3 years.

Results: The accumulation of RAC2 subunit genotypes TA/AA among cases was statistically significant upon adjustment for gender, age and doxorubicin dose in a multivariate logistic regression analysis (OR: 2.3, p = 0.028; univariate: OR: 1.8, p = 0.077). RAC2 and CYBA genotypes were significantly associated with anthracycline-induced cardiotoxicity in a meta-analysis of this and a similar previous study.

Conclusion: Our results support the theory that NADPH oxidase is involved in anthracycline-induced cardiotoxicity. Original submitted 9 July 2014; Revision submitted 19 December 2014.

Keywords: RICOVER-60; SNP; anthracyclines; cardiotoxicity; clinical trial; heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anthracyclines / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Cardiotoxicity / genetics*
  • Cardiotoxicity / pathology
  • Cyclophosphamide / adverse effects
  • Doxorubicin / adverse effects
  • Female
  • Genetic Association Studies
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / genetics
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • NADPH Oxidases / genetics*
  • Polymorphism, Single Nucleotide
  • Prednisone / adverse effects
  • RAC2 GTP-Binding Protein
  • Rituximab / adverse effects
  • Vincristine / adverse effects
  • rac GTP-Binding Proteins / genetics*

Substances

  • ABCC2 protein, human
  • Anthracyclines
  • Multidrug Resistance-Associated Protein 2
  • Rituximab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • NADPH Oxidases
  • CYBA protein, human
  • rac GTP-Binding Proteins
  • Prednisone

Supplementary concepts

  • CHOP protocol