A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

E.A. Hungate, S.R. Vora, E.R. Gamazon, T. Moriyama, T. Best, I. Hulur, Y. Lee, T.J. Evans, E. Ellinghaus, M. Stanulla, J. Rudant, L. Orsi, J. Clavel, Elizabeth Milne, R.J. Scott, C.H. Pui, N.J. Cox, M.L. Loh, J.J. Yang, A.D. Skol & 1 others K. Onel

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© 2016, Nature Publishing Group. All rights reserved. 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.
Original languageEnglish
Pages (from-to)10635
JournalNature Communications
Publication statusPublished - 2016


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