Genetic Contribution to Treatment-Related Dyslipidemia in Adult Survivors of Childhood Cancer: Findings from the CCSS, SJLIFE, and DCCSS-LATER Cohorts

BACKGROUND Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication. METHODS Discovery analysis was performed in the Original Childhood Cancer Survivor Study (CCSS) cohort (N=4,332). Replication analyses were carried out in the CCSS Expansion cohort (N=2,212), the St Jude Lifetime Cohort (SJLIFE, N=2,829), and the DCCSS-LATER Cohort (N=1,814). In the CCSS cohorts, dyslipidemia was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 self-reported high cholesterol or high triglycerides, whereas in SJLIFE and DCCSS-LATER, it was assessed by serum lipid measurements. Association analysis was performed in the entire cohort and stratified by cancer treatment. RESULTS The initial discovery analysis yielded one genome-wide significant (p<5x10-8) and 16 suggestive (p<5x10-6) loci associated with dyslipidemia risk. Of these, one genome-wide significant and eight suggestive loci with biological plausibility were selected for replication analysis, but none replicated. Additionally, treatment-stratified analysis revealed six significant (p<5x10-8) loci, none of which replicated in meta-analysis. CONCLUSIONS Further research with clinically assessed data and larger sample sizes is needed to explore the genetic contributions to dyslipidemia risk in childhood cancer survivors. IMPACT The establishment of larger, internationally collaborative consortia of childhood cancer survivors is critical for generating more robust findings, which will help the identification of those survivors at risk for dyslipidemia and subsequently cardiovascular disease.