title: Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199.
abstract: OBJECTIVE
  Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN.
  
  
  METHODS
  We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199.
  
  
  RESULTS
  When evaluating for grade 3-4 TIPN, 120 SNPs had a P value of <10(-4) from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3-4 TIPN (P = 1.7 × 10(-3); OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2-4 TIPN (HR, 2.1; P = 5.6 × 10(-16)) and grade 3-4 TIPN (HR, 2.6; P = 1.1 × 10(-11)) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10(-7)).
  
  
  CONCLUSIONS
  rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
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: Milan
authors.initials: M
authors.lastname: Radovich
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: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
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: Gail
authors.initials: G
authors.lastname: Vance
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: Matteo
authors.initials: M
authors.lastname: Vatta
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Shaochun
authors.initials: S
authors.lastname: Bai
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Daniel
authors.initials: D
authors.lastname: Koller
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Neill
authors.affiliation: Research Advocacy Network, Plano, Texas.
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Research Advocacy Network, Plano, Texas.
authors.forename: Elda
authors.initials: E
authors.lastname: Railey
authors.affiliation: CB White, Chicago, Illinois.
authors.forename: Carol
authors.initials: C
authors.lastname: White
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ann
authors.initials: A
authors.lastname: Partridge
authors.affiliation: Albert Einstein university, Montefiore Medical Center, Bronx, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sparano
authors.affiliation: University of Pittsburgh Cancer Center, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Stanford University Medical Center, Stanford, California.
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D044383:Black People / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011961:Receptors, Fc / Q000235:genetics*; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D044465:White People / Q000235:genetics
chemical_list: D001952:Bridged-Ring Compounds; C526790:Fcalpha-mu receptor, human; D011961:Receptors, Fc; D043823:Taxoids; C080625:taxane