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Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors: A Report From COG-ALTE03N1, BMTSS,
Noha Sharafeldin1, Liting Zhou1, Purnima Singh1
1Institute for Cancer Outcomes and Survivorship, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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.
Insights
This study identified gene-level single nucleotide polymorphism (SNP) associations with cancer treatment-induced cardiomyopathy. The P2RX7 gene variant may offer a therapeutic target to reduce cardiac risk in survivors.
Area of Science:
- Genetics
- Oncology
- Cardiology
Background:
- Anthracyclines are effective cancer treatments but increase cardiomyopathy risk.
- This risk is linked to single nucleotide polymorphisms (SNPs), but gene-level interactions are unexamined.
Purpose of the Study:
- To investigate gene-level SNP associations with cardiomyopathy in cancer survivors.
- To identify potential genetic targets for mitigating cardiac toxicity.
Main Methods:
- Whole-exome sequencing data from 278 childhood cancer survivors (COG study ALTE03N1).
- Logic regression for gene-level SNP combinations and ordinal logistic regression for associations.
- Replication in three independent survivor cohorts (COG, BMTSS, CCSS).
Main Results:
- Gene-level association for P2RX7 (rs71711963) with reduced cardiomyopathy risk was identified and replicated.
- Additional signals found in TNIK, LRRK2, MEFV, NOBOX, and FBN3.
- Individual SNPs from discovery genes (except FBN3) were replicated.
Conclusions:
- SNP sets with P2RX7 variant alleles are associated with decreased cardiomyopathy risk.
- P2RX7 variants represent a potential therapeutic target for managing cardiac outcomes in cancer survivors.
