A novel locus on 6p21.2 for cancer treatment-induced cardiac dysfunction among childhood cancer survivors
Menée aux Etats-Unis à partir de données de séquençage du génome entier portant sur 1 870 patients d'ascendance européenne ayant survécu à un cancer pédiatrique et inclus dans "the St. Jude Lifetime Cohort", puis validée sur 301 patients d'ascendance africaine inclus dans la même cohorte et sur 4 020 patients d'ascendance européenne inclus dans "the Childhood Cancer Survivor Study", cette étude identifie un nouveau locus de susceptibilité au risque de dysfonctionnement cardiaque lié aux traitements anticancéreux
Background : Adult survivors of childhood cancer are at increased risk of cardiac late effects. Methods : Using whole-genome sequencing data from 1,870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Significant findings were validated in 301 SJLIFE survivors of African ancestry and 4,020 survivors of European ancestry from the Childhood Cancer Survivor Study (CCSS). All statistical tests were 2-sided. Results : A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10–8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction: 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe/disabling or life-threatening CCD and replicated in 4,020 CCSS survivors of European ancestry (OR = 1.40; P = .039). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1,651 SJLIFE survivors of European ancestry showed significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA-sequencing of 75 survivors. Conclusions : Leveraging the two largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association.