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

Overview

Journal JACC CardioOncol

Specialty Cardiology & Vascular Diseases

Date 2024 Jan 11

PMID 38205005

Authors

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

Affiliations

Soon will be listed here.

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 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 (OR: 0.10; 95% CI: 0.04-0.27; = 2.19 × 10) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; = 0.009) in the CCSS cohort. Additional signals were identified on , , , , and . Individual SNPs across all discovery genes, except , were replicated.

Conclusions: In our study, SNP sets having 1 or no copies of variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.

Citing Articles

Genetic Background in Patients with Cancer Therapy-Induced Cardiomyopathy.

Fazzini L, Campana N, Cossu S, Deidda M, Madaudo C, Quagliariello V J Clin Med. 2025; 14(4).

PMID: 40004816 PMC: 11856774. DOI: 10.3390/jcm14041286.

Genetic Susceptibility for Anthracycline-Induced Cardiomyopathy: Novel Insights by Combining SNPs.

Leerink J, Feijen E, Kremer L JACC CardioOncol. 2024; 5(6):819-820.

PMID: 38205009 PMC: 10774778. DOI: 10.1016/j.jaccao.2023.08.002.

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