title: Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure.
abstract: OBJECTIVE
  Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.
  
  
  METHODS
  We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.
  
  
  RESULTS
  When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2).
  
  
  CONCLUSIONS
  rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43-51. ©2016 AACR.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana. bpschnei@iupui.edu.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Fei
authors.initials: F
authors.lastname: Shen
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Laura
authors.initials: L
authors.lastname: Gardner
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Milan
authors.initials: M
authors.lastname: Radovich
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Guanglong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.affiliation: Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, Massachusetts.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: Albert Einstein University, Montefiore Medical Center, Bronx, New York.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: University of Pittsburgh Cancer Center, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Edinburgh Cancer Research Centre, Edinburgh, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Irmina
authors.initials: I
authors.lastname: Gradus-Pizlo
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Mastouri
authors.affiliation: Swiss Cardiovascular Center, Bern University Hospital, Inselspital, Bern, Switzerland.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Suter
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D018943:Anthracyclines / Q000009:adverse effects* / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy; D016022:Case-Control Studies; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015203:Reproducibility of Results; D018570:Risk Assessment
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic