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 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 Haberle; Richard M. Weinshilboum; Liewei Wang

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

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

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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 language	English (US)
Pages (from-to)	3342-3355
Number of pages	14
Journal	Clinical Cancer Research
Volume	28
Issue number	15
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4774
State	Published - Aug 1 2022
Externally published	Yes

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© 2022 American Association for Cancer Research Inc.. All rights reserved.

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Fasching, P. A., Liu, D., Scully, S., Ingle, J. N., Lyra, P. C., Rack, B., Hein, A., Ekici, A. B., Reis, A., Schneeweiss, A., Tesch, H., Fehm, T. N., Heinrich, G., Beckmann, M. W., Ruebner, M., Huebner, H., Lambrechts, D., Madden, E., Shen, J., ... 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

Fasching, PA, 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, MW, Ruebner, M, Huebner, H, Lambrechts, D, Madden, E, Shen, J, Romm, J, Doheny, K, Jenkins, GD, Carlson, EE, Li, L, Fridley, BL, Cunningham, JM, Janni, W, Monteiro, ANA, Schaid, DJ, Haberle, L, Weinshilboum, RM & Wang, L 2022, 'Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer', Clinical Cancer Research, vol. 28, no. 15, pp. 3342-3355. https://doi.org/10.1158/1078-0432.CCR-20-4774

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title = "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 theMHCI regulator NLRC5 implies the possible involvement of immuno-oncological pathways.",

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

year = "2022",

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doi = "10.1158/1078-0432.CCR-20-4774",

language = "English (US)",

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pages = "3342--3355",

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TY - JOUR

T1 - Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer

AU - Fasching, Peter A.

AU - Liu, Duan

AU - Scully, Steve

AU - Ingle, James N.

AU - Lyra, Paulo C.

AU - Rack, Brigitte

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Reis, Andre

AU - Schneeweiss, Andreas

AU - Tesch, Hans

AU - Fehm, Tanja N.

AU - Heinrich, Georg

AU - Beckmann, Matthias W.

AU - Ruebner, Matthias

AU - Huebner, Hanna

AU - Lambrechts, Diether

AU - Madden, Ebony

AU - Shen, Jess

AU - Romm, Jane

AU - Doheny, Kim

AU - Jenkins, Gregory D.

AU - Carlson, Erin E.

AU - Li, Liang

AU - Fridley, Brooke L.

AU - Cunningham, Julie M.

AU - Janni, Wolfgang

AU - Monteiro, Alvaro N.A.

AU - Schaid, Daniel J.

AU - Haberle, Lothar

AU - Weinshilboum, Richard M.

AU - Wang, Liewei

PY - 2022/8/1

Y1 - 2022/8/1

N2 - 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.

AB - 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.

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AN - SCOPUS:85135596701

SN - 1078-0432

VL - 28

SP - 3342

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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ER -

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

Abstract

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