Genomics of Long‐Term Complications of Childhood Leukemia: Rationale and Design of the GenLEA Study

BACKGROUND: Survivors of childhood acute leukemia are at risk of long-term treatment-related complications, but the role of genetic susceptibility remains unclear. We describe here the GenLEA project, which was established to investigate genetic determinants of long-term complications. METHODS: GenLEA builds on the French LEA cohort, which prospectively follows acute leukemia survivors since 2004 through standardized dedicated consultations every 2 to 4 years. Patients were selected from the nested CryoLEA biobank. Cases were defined as survivors with at least one of four major complications (anthracycline-related cardiomyopathy, secondary malignant neoplasms, metabolic syndrome, or osteonecrosis) while controls were survivors without these complications, selected with the objective of a 1:3 case-to-control ratio. Genetic data were generated using genome-wide genotyping and whole-exome sequencing. RESULTS: After quality control, 743 patients were included for analyses (241 cases and 502 controls). Fifty-one percent were male with a median age at diagnosis of 7.3 years (IQR 3.9-13.0), and median follow-up reached 14 years (IQR 7.9-19.8). Among the cases, 44 had cardiomyopathy, 50 osteonecrosis, 37 secondary malignant neoplasms, and 163 metabolic syndrome. Planned analyses include genome-wide association studies (GWAS) and downstream analyses such as transcriptome-wide association studies (TWAS) and Mendelian randomization on genotyping data, as well as gene-based tests on exome sequencing data. PERSPECTIVES: By integrating these approaches with high-quality clinical information, GenLEA offers a unique opportunity to identify molecular determinants of late complications after childhood acute leukemia. This collaborative resource will support replication efforts, meta-analyses, and ultimately the development of personalized long-term follow-up strategies.