title: Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation.
abstract: BACKGROUND
  Beyond estrogen receptor (ER), there are no validated predictors for tamoxifen (TAM) efficacy and toxicity. We utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular sensitivity to TAM.
  
  
  METHODS
  Our discovery model incorporates multidimensional datasets, including genome-wide genotype, gene expression, and endoxifen-induced cellular growth inhibition in the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide findings were further evaluated in NCI60 cancer cell lines. Gene knock-down experiments were performed in four breast cancer cell lines. Genetic variants identified in the cell-based model were examined in 245 Caucasian breast cancer patients who underwent TAM treatment.
  
  
  RESULTS
  We identified seven novel single-nucleotide polymorphisms (SNPs) associated with endoxifen sensitivity through the expression of 10 genes using the genome-wide integrative analysis. All 10 genes identified in LCLs were associated with TAM sensitivity in NCI60 cancer cell lines, including USP7. USP7 knock-down resulted in increasing resistance to TAM in four breast cancer cell lines tested, which is consistent with the finding in LCLs and in the NCI60 cells. Furthermore, we identified SNPs that were associated with TAM-induced toxicities in breast cancer patients, after adjusting for other clinical factors.
  
  
  CONCLUSIONS
  Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.
authors.affiliation: Department of Medicine.
authors.forename: L
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Medicine.
authors.forename: D
authors.initials: D
authors.lastname: Ziliak
authors.affiliation: Health Studies, University of Chicago, Chicago.
authors.forename: H K
authors.initials: HK
authors.lastname: Im
authors.affiliation: Department of Medicine.
authors.forename: E R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, USA.
authors.forename: S
authors.initials: S
authors.lastname: Philips
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Indiana University, Indianapolis, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Department of Medicine. Electronic address: rhuang@medicine.bsd.uchicago.edu.
authors.forename: R S
authors.initials: RS
authors.lastname: Huang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D047628:Estrogen Receptor alpha; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
keywords: HapMap; SNP; gene expression; genome-wide association study; tamoxifen