Year: 2023
Type: article
Study design: Observational Study
Abstract: 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. This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. 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. 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. 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.
Source: JACC CardioOncology
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
Institutions: University of Alabama at Birmingham, UAB Medicine, University of North Texas, University at Buffalo, State University of New York, Northwestern University, St. Jude Children's Research Hospital, Duke University, Seattle Children's Hospital, University of Washington, Fred Hutch Cancer Center, City Of Hope National Medical Center, City of Hope, University of Minnesota
Language: Finnish
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,396
Awards: G1151351497, G1504112592, G2457495176, G2679093195, G2901481919, Mitigating Long-term Treatment-related Morbidity in Childhood Cancer Survivors, G3272408970, G3647844574, Children's Oncology Group Statistics and Data Center, G4444553339, G5396914778, G5783149556, G609259107, G6631047179, G751896108, Children's Oncology Group NCI Community Oncology Research Program (NCORP) Research Base grant, G8483056892, G9000054886, G9000086855, Cancer Center Support Grant (CCSG), G997771125
OpenAlex ID: W4386776126