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

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 the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

• Authors: 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 Romm, Kim 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 Häberle, Richard M Weinshilboum, Liewei Wang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 15 Pg. 3342-3355 (08 02 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35653140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Intracellular Signaling Peptides and Proteins
• NLRC5 protein, human

Topics

• Breast Neoplasms (drug therapy, genetics)
• Female
• Genetic Loci
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Leukopenia (chemically induced, genetics)
• Polymorphism, Single Nucleotide