Clinical validation of genetic variants associated with in vitro chemotherapy-related lymphoblastoid cell toxicity

Peter A. Fasching, Lothar Häberle, Brigitte Rack, Liang Li, Alexander Hein, Arif B. Ekici, Andre Reis, Michael P. Lux, Julie M. Cunningham, Matthias Ruebner, Gergory Jenkins, Brooke Fridley, Andreas Schneeweiss, Hans Tesch, Werner Lichtenegger, Tanja Fehm, Georg Heinrich, Mahdi Rezai, Matthias W. Beckmann, Wolfgang JanniRichard M. Weinshilboum, Liewei Wang

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested. None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival. Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.

Original languageEnglish (US)
Pages (from-to)78133-78143
Number of pages11
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Chemotherapy
  • Leukopenia
  • Neutropenia
  • Polymorphism
  • SNP

ASJC Scopus subject areas

  • Oncology

Cite this

Fasching, P. A., Häberle, L., Rack, B., Li, L., Hein, A., Ekici, A. B., Reis, A., Lux, M. P., Cunningham, J. M., Ruebner, M., Jenkins, G., Fridley, B., Schneeweiss, A., Tesch, H., Lichtenegger, W., Fehm, T., Heinrich, G., Rezai, M., Beckmann, M. W., ... Wang, L. (2017). Clinical validation of genetic variants associated with in vitro chemotherapy-related lymphoblastoid cell toxicity. Oncotarget, 8(44), 78133-78143. https://doi.org/10.18632/oncotarget.17726