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Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Breast Cancer Patients.

Authors
  • Fasching, Peter A1
  • Liu, Duan2
  • Scully, Steve3
  • Ingle, James N4
  • Lyra, Paulo C5
  • Rack, Brigitte6
  • Hein, Alexander7
  • Ekici, Arif B8
  • Reis, André9
  • Schneeweiss, Andreas10
  • Tesch, Hans11
  • Fehm, Tanja N12
  • Heinrich, Georg13
  • Beckmann, Matthias W14
  • Ruebner, Matthias15
  • Huebner, Hanna16
  • Lambrechts, Diether17
  • Madden, Ebony18
  • Shen, Jess19
  • Romm, Jane20
  • And 12 more
  • 1 Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany. , (Germany)
  • 2 Mayo Clinic, Rochester, United States. , (United States)
  • 3 NA, Rochester, MN, United States. , (United States)
  • 4 Mayo Clinic, Rochester, MN, United States. , (United States)
  • 5 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States. , (United States)
  • 6 University Hospital Ulm, Germany. , (Germany)
  • 7 Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Bavaria, Germany. , (Germany)
  • 8 Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. , (Germany)
  • 9 Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. , (Germany)
  • 10 National Center for Tumor Diseases, Heidelberg, Germany. , (Germany)
  • 11 Onkologie Bethanien, Frankfurt, Germany. , (Germany)
  • 12 Universitätsklinikum Düsseldorf.
  • 13 Doctor's office of Dr. G. Heinrich, Fürstenwalde, Germany. , (Germany)
  • 14 Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany. , (Germany)
  • 15 University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Bavaria, Germany. , (Germany)
  • 16 University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany. , (Germany)
  • 17 VIB Center for Cancer Biology, Leuven, Belgium. , (Belgium)
  • 18 National Human Genome Research Institute, Bethesda, United States. , (United States)
  • 19 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada. , (Canada)
  • 20 Johns Hopkins University, Baltimore, MD, United States. , (United States)
  • 21 Johns Hopkins School of Medicine, Baltimore, MD, United States. , (United States)
  • 22 Insitiute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China. , (China)
  • 23 Moffitt Cancer Center, Tampa, FL, United States. , (United States)
  • 24 University Hospital Ulm, Ulm, Baden-Wuerttemberg, Germany. , (Germany)
Type
Published Article
Journal
Clinical Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jun 02, 2022
Identifiers
DOI: 10.1158/1078-0432.CCR-20-4774
PMID: 35653140
Source
Medline
Language
English
License
Unknown

Abstract

To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLEs) after chemotherapy using a genome-wide association study (GWAS). A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the major histocompatibility complex I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

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