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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms8553

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

Journal article published in 2015 by Heng Xu, Hui Zhang, Wenjian Yang, Rachita Yadav, Alanna C. Morrison, Maoxiang Qian ORCID, Meenakshi Devidas, Yu Liu, Virginia Perez-Andreu, Xujie Zhao, Julie M. Gastier-Foster, Philip J. Lupo, Geoff Neale, Elizabeth Raetz, Eric Larsen and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractThere 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 p16INK4A, 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.