TY - JOUR
T1 - Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors
T2 - A Report From COG-ALTE03N1, BMTSS, and CCSS
AU - Sharafeldin, Noha
AU - Zhou, Liting
AU - Singh, Purnima
AU - Crossman, David K.
AU - Wang, Xuexia
AU - Hageman, Lindsey
AU - Landier, Wendy
AU - Blanco, Javier G.
AU - Burridge, Paul W.
AU - Sapkota, Yadav
AU - Yasui, Yutaka
AU - Armstrong, Gregory T.
AU - Robison, Leslie L.
AU - Hudson, Melissa M.
AU - Oeffinger, Kevin
AU - Chow, Eric J.
AU - Armenian, Saro H.
AU - Weisdorf, Daniel J.
AU - Bhatia, Smita
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/12
Y1 - 2023/12
N2 - Background: Anthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined. Objectives: This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. Methods: For discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children's Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10−6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively. Results: Median age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P = 2.19 × 10−6) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P = 0.009) in the CCSS cohort. Additional signals were identified on TNIK, LRRK2, MEFV, NOBOX, and FBN3. Individual SNPs across all discovery genes, except FBN3, were replicated. Conclusions: In our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.
AB - Background: Anthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined. Objectives: This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. Methods: For discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children's Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10−6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively. Results: Median age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P = 2.19 × 10−6) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P = 0.009) in the CCSS cohort. Additional signals were identified on TNIK, LRRK2, MEFV, NOBOX, and FBN3. Individual SNPs across all discovery genes, except FBN3, were replicated. Conclusions: In our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.
KW - anthracycline-induced cardiomyopathy
KW - childhood cancer survivors
KW - gene-level association
KW - purinergic receptor P2X7
KW - whole exome sequencing
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U2 - 10.1016/j.jaccao.2023.06.007
DO - 10.1016/j.jaccao.2023.06.007
M3 - Article
C2 - 38205005
AN - SCOPUS:85172921022
SN - 2666-0873
VL - 5
SP - 807
EP - 818
JO - JACC: CardioOncology
JF - JACC: CardioOncology
IS - 6
ER -
