Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

Purnima Singh; Disheet A. Shah; Mariam Jouni; Romina B. Cejas; David K. Crossman; Tarek Magdy; Shaowei Qiu; Xuexia Wang; Liting Zhou; Noha Sharafeldin; Lindsey Hageman; Donald E. McKenna; Saro H. Armenian; Frank M. Balis; Douglas S. Hawkins; Frank G. Keller; Melissa M. Hudson; Joseph P. Neglia; A. Kim Ritchey; Jill P. Ginsberg; Wendy Landier; Ravi Bhatia; Paul W. Burridge; Smita Bhatia

doi:10.1161/JAHA.123.029954

Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

Purnima Singh, Disheet A. Shah, Mariam Jouni, Romina B. Cejas, David K. Crossman, Tarek Magdy, Shaowei Qiu, Xuexia Wang, Liting Zhou, Noha Sharafeldin, Lindsey Hageman, Donald E. McKenna, Saro H. Armenian, Frank M. Balis, Douglas S. Hawkins, Frank G. Keller, Melissa M. Hudson, Joseph P. Neglia, A. Kim Ritchey, Jill P. GinsbergWendy Landier, Ravi Bhatia, Paul W. Burridge, Smita Bhatia^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. METHODS AND RESULTS: We designed a matched case-control study (Children’s Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/ Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. CONCLUSIONS: We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

Original language	English (US)
Article number	e029954
Journal	Journal of the American Heart Association
Volume	12
Issue number	19
DOIs	https://doi.org/10.1161/JAHA.123.029954
State	Published - Oct 3 2023

Funding

National Cancer Institute (NCI) (R35CA220502; Principal Investigator [PI]: S. Bhatia), Leukemia and Lymphoma Society (6563-19; PI: S. Bhatia), The V Foundation for Cancer Research (DT2019-010; PI: S. Bhatia), NCI (R01CA220002 and R01CA261898; PI: P.W. Burridge), The Children’s Oncology Group study reported here is supported by the National Clinical Trials Network Operations Center Grant (U10CA180886; PI: D.S. Hawkins); the National Clinical Trials Network Statistics & Data Center Grant (U10CA180899; PI: Alonzo); the Children’s Oncology Group Chair’s Grant (U10CA098543; PI: Adamson); The Children’s Oncology Group Statistics & Data Center Grant (U10CA098413; PI: Anderson); the NCI Community Oncology Research Program Grant (UG1CA189955; PI: Pollock); and the Community Clinical Oncology Program Grant (U10CA095861; PI: Pollock), and the St Baldrick’s Foundation through an unrestricted grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

anthracyclines
cardiomyopathy
childhood cancer survivors
gene expression
peripheral blood
transcriptome

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1161/JAHA.123.029954

Cite this

Singh, P., Shah, D. A., Jouni, M., Cejas, R. B., Crossman, D. K., Magdy, T., Qiu, S., Wang, X., Zhou, L., Sharafeldin, N., Hageman, L., McKenna, D. E., Armenian, S. H., Balis, F. M., Hawkins, D. S., Keller, F. G., Hudson, M. M., Neglia, J. P., Ritchey, A. K., ... Bhatia, S. (2023). Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report. Journal of the American Heart Association, 12(19), Article e029954. https://doi.org/10.1161/JAHA.123.029954

@article{1c243e6198e144bfa250d3c397270356,

title = "Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report",

abstract = "BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. METHODS AND RESULTS: We designed a matched case-control study (Children{\textquoteright}s Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/ Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. CONCLUSIONS: We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.",

keywords = "anthracyclines, cardiomyopathy, childhood cancer survivors, gene expression, peripheral blood, transcriptome",

author = "Purnima Singh and Shah, {Disheet A.} and Mariam Jouni and Cejas, {Romina B.} and Crossman, {David K.} and Tarek Magdy and Shaowei Qiu and Xuexia Wang and Liting Zhou and Noha Sharafeldin and Lindsey Hageman and McKenna, {Donald E.} and Armenian, {Saro H.} and Balis, {Frank M.} and Hawkins, {Douglas S.} and Keller, {Frank G.} and Hudson, {Melissa M.} and Neglia, {Joseph P.} and Ritchey, {A. Kim} and Ginsberg, {Jill P.} and Wendy Landier and Ravi Bhatia and Burridge, {Paul W.} and Smita Bhatia",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.",

year = "2023",

month = oct,

day = "3",

doi = "10.1161/JAHA.123.029954",

language = "English (US)",

volume = "12",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "American Heart Association Inc.",

number = "19",

}

Singh, P, Shah, DA, Jouni, M, Cejas, RB, Crossman, DK, Magdy, T, Qiu, S, Wang, X, Zhou, L, Sharafeldin, N, Hageman, L, McKenna, DE, Armenian, SH, Balis, FM, Hawkins, DS, Keller, FG, Hudson, MM, Neglia, JP, Ritchey, AK, Ginsberg, JP, Landier, W, Bhatia, R, Burridge, PW & Bhatia, S 2023, 'Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report', Journal of the American Heart Association, vol. 12, no. 19, e029954. https://doi.org/10.1161/JAHA.123.029954

TY - JOUR

T1 - Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

AU - Singh, Purnima

AU - Shah, Disheet A.

AU - Jouni, Mariam

AU - Cejas, Romina B.

AU - Crossman, David K.

AU - Magdy, Tarek

AU - Qiu, Shaowei

AU - Wang, Xuexia

AU - Zhou, Liting

AU - Sharafeldin, Noha

AU - Hageman, Lindsey

AU - McKenna, Donald E.

AU - Armenian, Saro H.

AU - Balis, Frank M.

AU - Hawkins, Douglas S.

AU - Keller, Frank G.

AU - Hudson, Melissa M.

AU - Neglia, Joseph P.

AU - Ritchey, A. Kim

AU - Ginsberg, Jill P.

AU - Landier, Wendy

AU - Bhatia, Ravi

AU - Burridge, Paul W.

AU - Bhatia, Smita

PY - 2023/10/3

Y1 - 2023/10/3

N2 - BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. METHODS AND RESULTS: We designed a matched case-control study (Children’s Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/ Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. CONCLUSIONS: We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

AB - BACKGROUND: Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. METHODS AND RESULTS: We designed a matched case-control study (Children’s Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/ Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified “hepatic fibrosis” and “iron homeostasis” pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. CONCLUSIONS: We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.

KW - anthracyclines

KW - cardiomyopathy

KW - childhood cancer survivors

KW - gene expression

KW - peripheral blood

KW - transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85174641451&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85174641451&partnerID=8YFLogxK

U2 - 10.1161/JAHA.123.029954

DO - 10.1161/JAHA.123.029954

M3 - Article

C2 - 37750583

AN - SCOPUS:85174641451

SN - 2047-9980

VL - 12

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 19

M1 - e029954

ER -

Altered Peripheral Blood Gene Expression in Childhood Cancer Survivors With Anthracycline-Induced Cardiomyopathy – A COG-ALTE03N1 Report

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this