Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors: A Report From COG-ALTE03N1, BMTSS, and CCSS

Noha Sharafeldin; Liting Zhou; Purnima Singh; David K Crossman; Xuexia Wang; Lindsey Hageman; Wendy Landier; Javier G Blanco; Paul W Burridge; Yadav Sapkota; Yutaka Yasui; Gregory T Armstrong; Leslie L Robison; Melissa M Hudson; Kevin Oeffinger; Eric J Chow; Saro H Armenian; Daniel J Weisdorf; Smita Bhatia

doi:10.1016/j.jaccao.2023.06.007

Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors: A Report From COG-ALTE03N1, BMTSS, and CCSS

JACC CardioOncol. 2023 Sep 14;5(6):807-818. doi: 10.1016/j.jaccao.2023.06.007. eCollection 2023 Dec.

Authors

Noha Sharafeldin¹, Liting Zhou¹, Purnima Singh¹, David K Crossman², Xuexia Wang³, Lindsey Hageman¹, Wendy Landier¹, Javier G Blanco⁴, Paul W Burridge⁵, Yadav Sapkota⁶, Yutaka Yasui⁶, Gregory T Armstrong⁶, Leslie L Robison⁶, Melissa M Hudson⁶, Kevin Oeffinger⁷, Eric J Chow⁸, Saro H Armenian⁹, Daniel J Weisdorf¹⁰, Smita Bhatia¹

Affiliations

¹ Institute for Cancer Outcomes and Survivorship, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
² Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
³ Department of Mathematics, University of North Texas, Denton, Texas, USA.
⁴ The State University of New York at Buffalo, Buffalo, New York, USA.
⁵ Department of Pharmacology, Northwestern University, Chicago, Illinois, USA.
⁶ St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁷ Duke University, Durham, North Carolina, USA.
⁸ Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
⁹ Department of Population Sciences, City of Hope, Duarte, California, USA.
¹⁰ Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

Abstract

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.

Keywords: anthracycline-induced cardiomyopathy; childhood cancer survivors; gene-level association; purinergic receptor P2X7; whole exome sequencing.

Abstract

Grants and funding