Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer-Reference-Cited by-同舟云学术

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

Published:2022-06-02 Issue:15 Volume:28 Page:3342-3355
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Fasching Peter A.¹^ORCID,Liu Duan²^ORCID,Scully Steve²,Ingle James N.³^ORCID,Lyra Paulo C.⁴^ORCID,Rack Brigitte⁵,Hein Alexander¹^ORCID,Ekici Arif B.⁶^ORCID,Reis Andre⁶^ORCID,Schneeweiss Andreas⁷^ORCID,Tesch Hans⁸,Fehm Tanja N.⁹,Heinrich Georg¹⁰,Beckmann Matthias W.¹,Ruebner Matthias¹,Huebner Hanna¹,Lambrechts Diether¹¹^ORCID,Madden Ebony¹²,Shen Jess¹³,Romm Jane¹⁴,Doheny Kim¹⁴,Jenkins Gregory D.¹⁵,Carlson Erin E.¹⁵,Li Liang²¹⁶^ORCID,Fridley Brooke L.¹⁷^ORCID,Cunningham Julie M.¹⁸^ORCID,Janni Wolfgang⁵^ORCID,Monteiro Alvaro N.A.¹⁹^ORCID,Schaid Daniel J.¹⁵,Häberle Lothar¹²⁰,Weinshilboum Richard M.²,Wang Liewei²

Affiliation:

1. 1Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany.

2. 2Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.

3. 3Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.

4. 4Biotechnology/RENORBIO Program, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil.

5. 5Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany.

6. 6Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

7. 7National Center for Tumor Diseases, Division of Gynecologic Oncology, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany.

8. 8Onkologie Bethanien, Frankfurt am Main, Germany.

9. 9Department of Gynecology and Obstetrics, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany.

10. 10Schwerpunktpraxis für Gynäkologische Onkologie, Fürstenwalde, Germany.

11. 11VIB Center for Cancer Biology, VIB and Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.

12. 12Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland.

13. 13Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

14. 14McKusick-Nathans Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland.

15. 15Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

16. 16Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tiantan Xili, Beijing, China.

17. 17Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.

18. 18Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

19. 19Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

20. 20Department of Gynecology and Obstetrics, Unit of Biostatistics, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Abstract

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.

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-20-4774/3164498/ccr-20-4774.pdf

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