Oncotarget

Clinical Research Papers:

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 Janni, Richard M. Weinshilboum and Liewei Wang

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Oncotarget. 2017; 8:78133-78143. https://doi.org/10.18632/oncotarget.17726

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Abstract

Peter A. Fasching1,2,*, Lothar Häberle1,3,*, Brigitte Rack4, Liang Li5,6, Alexander Hein1, Arif B. Ekici7, Andre Reis7, Michael P. Lux1, Julie M. Cunningham8, Matthias Ruebner1, Gergory Jenkins9, Brooke Fridley9,10, Andreas Schneeweiss11, Hans Tesch12, Werner Lichtenegger13, Tanja Fehm14, Georg Heinrich15, Mahdi Rezai16, Matthias W. Beckmann1, Wolfgang Janni17, Richard M. Weinshilboum5 and Liewei Wang5

1Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

2Department of Medicine, Division of Hematology/Oncology, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA

3Department of Gynecology and Obstetrics, Biostatistics Unit, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

4Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Munich, Germany

5Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA

6Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

7Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

8Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA

9Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

10Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA

11Division of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany

12Department of Oncology, Onkologie Bethanien, Frankfurt, Germany

13Department of Gynecology and Obstetrics, Charité University Hospital, Campus Virchow, Berlin, Germany

14Department of Gynecology and Obstetrics, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany

15Department of Gynecologic Oncology, Schwerpunktpraxis für Gynäkologische Onkologie, Fürstenwalde, Germany

16Department of Breast Diseases, Breast Center of Düsseldorf, Luisenkrankenhaus, Düsseldorf, Germany

17Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany

*These authors have contributed equally to this work

Correspondence to:

Peter Fasching, email: [email protected]

Keywords: chemotherapy, neutropenia, leukopenia, SNP, polymorphism

Received: January 05, 2017     Accepted: April 06, 2017     Published: May 09, 2017

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.


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