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.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Oncogene Proteins, Fusion / genetics*
  • Pre-B-Cell Leukemia Transcription Factor 1 / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Oncogene Proteins, Fusion
  • Pre-B-Cell Leukemia Transcription Factor 1
  • TCF3 protein, human
  • TCF3-PBX1 fusion protein, human
  • PBX1 protein, human