Identification of Anthracycline-Induced Cardiotoxic Susceptible Loci in Childhood Cancer Survivors
Abstract
While the number of childhood cancer survivors has increased significantly with the introduction of anthracyclines as a chemotherapeutic agent, adverse and premature cardiovascular events have also increased in frequency in this population due to the known cardiotoxic effects of anthracyclines. This study measured genetic variation in a multiethnic cohort of childhood cancer survivors (n = 1138) treated with anthracyclines and seen at either University of Texas MD Anderson Cancer Center or Texas Children’s Hospital in Houston, Texas. Cardiotoxicity cases (n = 259) and controls (n = 879) were retrospectively determined based upon electronic medical record review for cardiac outcomes with a mean follow-up time of 12.8 years. Through the hypothesis-free approach of a genome wide association study, six loci were identified as potentially associated with increased risk of cardiotoxicity with 10 - 25% increased odds. In the main effect analysis across all ethnic/racial populations, no variants were identified as significant, but six variants were trending towards significance (p < 1x10-5). The top variants detected have not been previously identified in the literature as cardiotoxicity risk alleles. Top cardiotoxicity susceptibility alleles included DMD:rs2032418 (OR (95% CI): 1.17 (1.10 - 1.24), p = 1.33x10-6) and MCF2L:rs7318580 (OR (95% CI): 1.10 (1.06 - 1.15), p = 6.44x10-6). An intron variant within the long non-coding RNA gene OFCC1:rs78324746 (OR (95% CI): 1.25 (1.13 - 1.37), p = 9.21x10-6) was identified in both the main effect analysis and was significant in the nonHispanic white survivor population. Literature supports potential cardiac roles for five of the six variants through developmental or cellular response pathways. Present knowledge of cardiotoxicity risk loci do not include cardiac developmental pathways. These novel loci may predispose childhood cancer survivors to adverse cardiovascular manifestations after environmental stresses such as anthracycline exposure. Further analysis of these findings may help to shape genetic considerations regarding risk stratification screening for cardiotoxicity in childhood cancer survivors exposed to anthracyclines.
Subject Area
Public health|Medicine|Pharmacology
Recommended Citation
Boies, Lori N, "Identification of Anthracycline-Induced Cardiotoxic Susceptible Loci in Childhood Cancer Survivors" (2021). Texas Medical Center Dissertations (via ProQuest). AAI30313365.
https://digitalcommons.library.tmc.edu/dissertations/AAI30313365