Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children

Lee SHR, Qian M, Yang W, Diedrich JD, Raetz E, Yang W, Dong Q, Devidas M, Pei D, Yeoh A, Cheng C, Pui CH, Evans WE, Mullighan CG, Hunger SP, Savic D, Relling MV, Loh ML, Yang JJ. Genome-Wide Association Study of Susceptibility Loci for TCF3-PBX1 Acute Lymphoblastic Leukemia in Children. J Natl Cancer Inst. 2021 Jul 1;113(7):933-937. doi: 10.1093/jnci/djaa133. PMID: 32882024; PMCID: PMC8487647.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10–8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10–8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.