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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.
B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.