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

Nat Commun. 2016 Feb 12;7:10635. doi: 10.1038/ncomms10635.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Black or African American / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 9 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Hispanic or Latino / genetics
  • Humans
  • Infant
  • Male
  • Polymorphism, Single Nucleotide
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • White People / genetics

Substances

  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15