A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Nat Genet. 2015 Sep;47(9):1079-84. doi: 10.1038/ng.3374. Epub 2015 Aug 3.

Abstract

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anthracyclines / adverse effects*
  • Anthracyclines / therapeutic use
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / therapeutic use
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Polymorphism, Single Nucleotide
  • Receptors, Retinoic Acid / genetics*
  • Rhabdomyosarcoma / drug therapy
  • Rhabdomyosarcoma / genetics
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / genetics
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / genetics*

Substances

  • Anthracyclines
  • Antibiotics, Antineoplastic
  • Receptors, Retinoic Acid
  • retinoic acid receptor gamma