Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia
Menée sur 2 535 enfants atteints d'une leucémie lymphoblastique aiguë, cette étude identifie des polymorphismes à simple nucléotide associés au risque de récidive de la maladie
Using risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the last 40 years. However, a substantial portion of patients experience relapse, many of whom have no known risk factors. Taking a genome-wide approach, we evaluated the relationships between genotypes at 444,044 SNPs with the risk of relapse in 2,535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual diseases (MRD), and 111 were significant even among patients who achieved negative MRD after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P=6.7×10-9). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In conclusion, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some also influenced outcome by affecting host disposition of antileukemic drugs.All trials are registered at clinicaltrials.gov or cancer.gov: COG P9904: NCT00005585, COG P9905: NCT00005596, COG P9906: NCT00005603, St. Jude Total XIIIB: NCI-T93-0101D, St. Jude Total XV: NCT00137111
Blood , résumé, 2012