Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation

L. Weng, D. Ziliak, H. K. Im, E. R. Gamazon, S. Philips, A. T. Nguyen, Zeruesenay Desta, Todd Skaar, D. A. Flockhart, R. S. Huang

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Design: 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. Conclusion: Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.

Original languageEnglish
Article numbermdt125
Pages (from-to)1867-1873
Number of pages7
JournalAnnals of Oncology
Volume24
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Tamoxifen
Genome
Cell Line
Breast Neoplasms
Single Nucleotide Polymorphism
HapMap Project
Gene Knockdown Techniques
Gene Expression
Pharmacogenetics
Estrogen Receptors
Neoplasms
Genotype
Growth
Genes

Keywords

  • Gene expression
  • Genome-wide association study
  • HapMap
  • SNP
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Weng, L., Ziliak, D., Im, H. K., Gamazon, E. R., Philips, S., Nguyen, A. T., ... Huang, R. S. (2013). Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation. Annals of Oncology, 24(7), 1867-1873. [mdt125]. https://doi.org/10.1093/annonc/mdt125

Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation. / Weng, L.; Ziliak, D.; Im, H. K.; Gamazon, E. R.; Philips, S.; Nguyen, A. T.; Desta, Zeruesenay; Skaar, Todd; Flockhart, D. A.; Huang, R. S.

In: Annals of Oncology, Vol. 24, No. 7, mdt125, 07.2013, p. 1867-1873.

Research output: Contribution to journalArticle

Weng, L, Ziliak, D, Im, HK, Gamazon, ER, Philips, S, Nguyen, AT, Desta, Z, Skaar, T, Flockhart, DA & Huang, RS 2013, 'Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation', Annals of Oncology, vol. 24, no. 7, mdt125, pp. 1867-1873. https://doi.org/10.1093/annonc/mdt125
Weng, L. ; Ziliak, D. ; Im, H. K. ; Gamazon, E. R. ; Philips, S. ; Nguyen, A. T. ; Desta, Zeruesenay ; Skaar, Todd ; Flockhart, D. A. ; Huang, R. S. / Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation. In: Annals of Oncology. 2013 ; Vol. 24, No. 7. pp. 1867-1873.
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