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Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

  • Author(s): Vijayakrishnan, Jayaram
  • Qian, Maoxiang
  • Studd, James B
  • Yang, Wenjian
  • Kinnersley, Ben
  • Law, Philip J
  • Broderick, Peter
  • Raetz, Elizabeth A
  • Allan, James
  • Pui, Ching-Hon
  • Vora, Ajay
  • Evans, William E
  • Moorman, Anthony
  • Yeoh, Allen
  • Yang, Wentao
  • Li, Chunliang
  • Bartram, Claus R
  • Mullighan, Charles G
  • Zimmerman, Martin
  • Hunger, Stephen P
  • Schrappe, Martin
  • Relling, Mary V
  • Stanulla, Martin
  • Loh, Mignon L
  • Houlston, Richard S
  • Yang, Jun J
  • et al.
Abstract

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

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