Xu, H.Zhang, H.Yang, W.Yadav, R.Morrison, A.Qian, M.Devidas, M.Liu, Y.Perez-Andreu, V.Zhao, X.Gastier-Foster, J.Lupo, P.Neale, G.Raetz, E.Larsen, E.Bowman, W.Carroll, W.Winick, N.Williams, R.Hansen, T.et al.2017-04-122017-04-122015Nature Communications, 2015; 6(1):7553-1-7553-72041-17232041-1723http://hdl.handle.net/2440/104445There 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.en© 2015 Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Genetic Predisposition to DiseaseJournal article003006119810.1038/ncomms85530003571803000022-s2.0-84933060281277135Mullighan, C. [0000-0002-1871-1850]