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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.

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