Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

Nat Commun. 2015 Jun 24;6:7553. doi: 10.1038/ncomms8553.

Abstract

There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Case-Control Studies
  • Child
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA-Binding Proteins / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Genotype
  • Germ-Line Mutation
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Ikaros Transcription Factor / genetics
  • Mice
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Transcription Factors / genetics

Substances

  • ARID5B protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • IKZF1 protein, human
  • Transcription Factors
  • Ikaros Transcription Factor

Grant support