Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

Abstract

Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of <i>PAX5</i>-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; <i>P =</i> 3.18 × 10^-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; <i>P</i> = 8.02 × 10^-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; <i>P</i> = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; <i>P</i> = 2.19 × 10^-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; <i>P</i> = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of <i>INO80</i> in <i>ETV6::RUNX1</i> ALL, <i>IKZF1</i>, and <i>CREBBP</i> in high-hyperdiploid ALL and <i>FHIT</i> in <i>BCR::ABL1</i>-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including <i>NRAS</i> and <i>CREBBP</i> in high-hyperdiploid ALL. Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.