Abstract
Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10−15, OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.
Highlights
Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-Acute lymphoblastic leukaemia (ALL)) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition
We found that all single-nucleotide polymorphisms (SNPs) in the locus found in GTEx are cis-eQTLs for CDKN2B, with increasing dosage of the risk allele associated with decreasing levels of CDKN2B mRNA (Padditive,rs77728904 1⁄4 6.1 Â 10 À 7 and Padditive,rs662463 1⁄4 8.7 Â 10 À 7; Fig. 3a and Supplementary Table 7)
We found that cJUN and CDKN2B expression was correlated in Africans in an rs662463-genotype-dependent manner (PLRT,twosided 1⁄4 0.02), the risk allele was associated with higher CDKN2B expression, which is inconsistent with our results in European ancestry individuals and our eQTL results
Summary
Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined 1⁄4 3.32 Â 10 À 15, OR 1⁄4 1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Within the last 10 years a number of loci have been identified by genome-wide association study (GWAS), which have shed considerable light on the genetics of BCP-ALL predisposition 9) and GATA3 (refs 10,11), all of which have odds ratios (ORs) ranging from 1.23 to 1.91 Their effect sizes are large relative to those of many of the variants identified for other complex diseases, these susceptibility loci explain only 8% of the genetic contribution to childhood BCP-ALL risk[4]. Our results shed light on genetic variation predisposing towards BCP-ALL, and suggest a path forward moving from GWAS associations to underlying mechanism
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