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

Fasching P, Liu D, Scully S, Ingle JN, Lyra PC, Rack B, Hein A, Ekici AB, Reis A, Schneeweiss A, Tesch H, Fehm TN, Heinrich G, Beckmann M, Rübner M, Hübner H, Lambrechts D, Madden E, Shen J, Romm J, Doheny K, Jenkins GD, Carlson EE, Li L, Fridley BL, Cunningham JM, Janni W, Monteiro AN, Schaid DJ, Häberle L, Weinshilboum RM, Wang L (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Clinical Cancer Research American Association for Cancer Research

Book Volume: 28

Pages Range: 3342-3355

Journal Issue: 15

DOI: 10.1158/1078-0432.CCR-20-4774

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.

Authors with CRIS profile

Peter Fasching Professur für Translationale Frauenheilkunde und Geburtshilfe Alexander Hein Department of Obstetrics and Gynaecology Arif Bülent Ekici Lehrstuhl für Humangenetik André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Matthias Beckmann Lehrstuhl für Geburtshilfe und Frauenheilkunde Matthias Rübner Department of Obstetrics and Gynaecology Hanna Hübner Department of Obstetrics and Gynaecology

Involved external institutions

Mayo Clinic US United States (USA) (US) Federal University of Espírito Santo / Universidade Federal do Espírito Santo (UFES) BR Brazil (BR) Universitätsklinikum Ulm DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Agaplesion Markus Krankenhaus DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) National Human Genome Research Institute (NHGRI) US United States (USA) (US) Mount Sinai Hospital (MSH) CA Canada (CA) Johns Hopkins University (JHU) US United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US)

How to cite

APA:

Fasching, P., Liu, D., Scully, S., Ingle, J.N., Lyra, P.C., Rack, B.,... Wang, L. (2022). Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer. Clinical Cancer Research, 28(15), 3342-3355. https://doi.org/10.1158/1078-0432.CCR-20-4774

MLA:

Fasching, Peter, et al. "Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer." Clinical Cancer Research 28.15 (2022): 3342-3355.

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