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

Peter A. Fasching, Duan Liu, Steve Scully, James N. Ingle, Paulo C. Lyra, Brigitte Rack, Alexander Hein, Arif B. Ekici, Andre Reis, Andreas Schneeweiss, Hans Tesch, Tanja N. Fehm, Georg Heinrich, Matthias W. Beckmann, Matthias Ruebner, Hanna Huebner, Diether Lambrechts, Ebony Madden, Jess Shen, Jane RommKim Doheny, Gregory D. Jenkins, Erin E. Carlson, Liang Li, Brooke L. Fridley, Julie M. Cunningham, Wolfgang Janni, Alvaro N.A. Monteiro, Daniel J. Schaid, Lothar Haberle, Richard M. Weinshilboum, Liewei Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). Experimental Design: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). 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. Results: 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. Conclusions: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of theMHCI regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

Original languageEnglish (US)
Pages (from-to)3342-3355
Number of pages14
JournalClinical Cancer Research
Volume28
Issue number15
DOIs
StatePublished - Aug 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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