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.
Highlights
TF analyses were performed on lead SNPs
clinical information was undertaken with informed consent
The diagnosis of ALL was established in accordance with World Health Organization guidelines
Summary
Medical Research Council UKALL97/99 trial by UK therapy centres and approval for UKALL2003 from the Scottish Multi-Centre Research Ethics Committee (REC:02/10/052), the UK Bloodwise Childhood Leukaemia Cell Bank, the United Kingdom Childhood Cancer Study, and University of Heidelberg; AALL0232 (clinicaltrials.gov NCT00075725)[54] and P9904/P9905/P9906 (NCT00005585/NCT00005596/ NCT00005603)[55] from the Children’s Oncology Group (COG); and Total Therapy XIIIB/XV (NCI-T93-0101D/NCT00137111)[56,57] from the St. Jude Children’s Research Hospital. Jude Total Therapy XIIIB/XV and 2057 non-ALL controls of European ancestry from the Multi-Ethnic Study of Atherosclerosis (MESA) study (dbGAP phs000209.v9)[13,18,20]
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