TY - JOUR
T1 - Genetic Contribution to Treatment-Related Dyslipidemia in Adult Survivors of Childhood Cancer
T2 - Findings from the CCSS, SJLIFE, and DCCSS-LATER Cohorts
AU - Bolier, Melissa
AU - Pluimakers, Vincent G.
AU - Broer, Linda
AU - Neggers, Sebastian J.C.M.M.
AU - de Winter, Demi T.C.
AU - Wang, Fan
AU - Baedke, Jessica L.
AU - Uitterlinden, André G.
AU - Petrykey, Kateryna
AU - Kremer, Leontien C.M.
AU - Loonen, Jacqueline J.
AU - Louwerens, Marloes
AU - van der Pal, Heleen J.
AU - Feijen, E. Lieke A.M.
AU - Oeffinger, Kevin C.
AU - Howell, Rebecca M.
AU - Chow, Eric J.
AU - Leisenring, Wendy M.
AU - Gramatges, Maria Monica M.
AU - Morton, Lindsay M.
AU - Robison, Leslie L.
AU - Hudson, Melissa M.
AU - Ness, Kirsten K.
AU - Sapkota, Yadav
AU - Armstrong, Gregory T.
AU - Bhatia, Smita
AU - Yasui, Yutaka
AU - van den Heuvel-Eibrink, Marry M.
N1 - Publisher Copyright:
©2025 The Authors; Published by the American Association for Cancer Research.
©2025 The Authors; Published by the American Association for Cancer Research.
PY - 2025/11/3
Y1 - 2025/11/3
N2 - 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 (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, dyslipidemia was defined as Common Terminology Criteria for Adverse Events grade 2 self-reported high cholesterol or high triglycerides, whereas in the St. Jude Lifetime and DCCSS-LATER cohorts, 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 < 5 × 10-8) and 16 suggestive (p < 5 × 10-6) 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 < 5 × 10-8) 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.
AB - 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 (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, dyslipidemia was defined as Common Terminology Criteria for Adverse Events grade 2 self-reported high cholesterol or high triglycerides, whereas in the St. Jude Lifetime and DCCSS-LATER cohorts, 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 < 5 × 10-8) and 16 suggestive (p < 5 × 10-6) 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 < 5 × 10-8) 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.
KW - Genome-Wide Association Study
KW - Neoplasms/therapy
KW - Humans
KW - Cancer Survivors/statistics & numerical data
KW - Adolescent
KW - Male
KW - Female
KW - Adult
KW - Dyslipidemias/genetics
KW - Child
KW - Cohort Studies
UR - https://www.scopus.com/pages/publications/105020804398
UR - https://www.mendeley.com/catalogue/5ac36b45-9f79-3548-9b56-45ec39567471/
U2 - 10.1158/1055-9965.EPI-25-0338
DO - 10.1158/1055-9965.EPI-25-0338
M3 - Article
C2 - 40853264
AN - SCOPUS:105020804398
SN - 1055-9965
VL - 34
SP - 2068
EP - 2076
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 11
ER -