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

Heng Xu, Hui Zhang, Wenjian Yang, Rachita Yadav, Alanna C Morrison, Maoxiang Qian, Meenakshi Devidas, Yu Liu, Virginia Perez-Andreu, Xujie Zhao, Julie M Gastier-Foster, Philip J Lupo, Geoff Neale, Elizabeth Raetz, Eric Larsen, W Paul Bowman, William L Carroll, Naomi Winick, Richard Williams, Torben HansenJens-Christian Holm, Elaine Mardis, Robert Fulton, Ching-Hon Pui, Jinghui Zhang, Charles G Mullighan, William E Evans, Stephen P Hunger, Ramneek Gupta, Kjeld Schmiegelow, Mignon L Loh, Mary V Relling, Jun J Yang

62 Citations (Scopus)


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.

Original languageEnglish
JournalNature Communications
Pages (from-to)7553
Publication statusPublished - 2015


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