Authors:
Hungate EA, Vora SR, Gamazon ER, Moriyama T, Best T, Hulur I, ... Milne E. et al.
Authors notes:
Nature Communications. 2016;7:10635.
Keywords:
Cancer Epidemiology, GWAS, paediatric acute lymphoblastic, B-cell precursor acute lymphoblastic leukaemia, European
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 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.
These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.