@article{c8f0750a25fc49edb4b410cb1e950dfe,
title = "Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children",
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.",
author = "Heng Xu and Hui Zhang and Wenjian Yang and Rachita Yadav and Morrison, {Alanna C.} and Maoxiang Qian and Meenakshi Devidas and Yu Liu and Virginia Perez-Andreu and Xujie Zhao and Gastier-Foster, {Julie M.} and Lupo, {Philip J.} and Geoff Neale and Elizabeth Raetz and Eric Larsen and Bowman, {W. Paul} and Carroll, {William L.} and Naomi Winick and Richard Williams and Torben Hansen and Holm, {Jens Christian} and Elaine Mardis and Robert Fulton and Pui, {Ching Hon} and Jinghui Zhang and Mullighan, {Charles G.} and Evans, {William E.} and Hunger, {Stephen P.} and Ramneek Gupta and Kjeld Schmiegelow and Loh, {Mignon L.} and Relling, {Mary V.} and Yang, {Jun J.}",
note = "Funding Information: We thank the patients and parents who participated in the clinical protocols included in this study and the clinicians and research staff at participating institutions. J.J.Y. is supported by the American Society of Hematology Scholar Award and by the Order of St. Francis Foundation. H.Z. is a St Baldrick{\textquoteright}s International Scholar. V.P.A is supported by the Spanish Ministry of Education Fellowship Grant and by the St Jude Children{\textquoteright}s Research Hospital Academic Programs Special Fellowship. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St Baldrick{\textquoteright}s Scholar. We thank M. Shriver (Pennsylvania State University) for sharing SNP genotype data of the Native American references and K. Nielsen (The Technical University of Denmark) for assistance with analysing the Danish dataset. This work was supported by the National Institutes of Health (grant numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729, CA176063, GM097119 and GM92666, HHSN261200800001E), the American Lebanese Syrian Associated Charities (ALSAC), the Danish Council for Strategic Research (TARGET (0603-00484B), BIOCHILD (0603-00457B)), the Region Zealand Health Scientific Research Foundation, Danish National Research Foundation, Danish Childhood Cancer Foundation, and Swedish Childhood Cancer Foundation. The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). Funding support for {\textquoteleft}Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium{\textquoteright} was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The authors also thank the staff and participants of the ARIC study for their important contributions. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = jun,
day = "24",
doi = "10.1038/ncomms8553",
language = "English",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}