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

TitleInherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.
Publication TypeJournal Article
Year of Publication2015
AuthorsXu H, Zhang H, Yang W, Yadav R, Morrison AC, Qian M, Devidas M, Liu Y, Perez-Andreu V, Zhao X, Gastier-Foster JM, Lupo PJ, Neale G, Raetz E, Larsen E, W Bowman P, Carroll WL, Winick N, Williams R, Hansen T, Holm J-C, Mardis E, Fulton R, Pui C-H, Zhang J, Mullighan CG, Evans WE, Hunger SP, Gupta R, Schmiegelow K, Loh ML, Relling MV
Secondary AuthorsYang JJ
JournalNat Commun
Volume6
Pagination7553
Date Published2015 Jun 24
ISSN2041-1723
KeywordsAnimals, Case-Control Studies, Child, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Germ-Line Mutation, HEK293 Cells, Hematopoietic Stem Cells, Humans, Ikaros Transcription Factor, Mice, Mutagenesis, Site-Directed, Mutation, Missense, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Transcription Factors
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.

DOI10.1038/ncomms8553
Alternate JournalNat Commun
PubMed ID26104880
PubMed Central IDPMC4544058
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R37 CA036401 / CA / NCI NIH HHS / United States
U10 CA098413 / CA / NCI NIH HHS / United States
U24 CA114766 / CA / NCI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
RC4 CA156449 / CA / NCI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 CA140729 / CA / NCI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
U10 CA098543 / CA / NCI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 CA036401 / CA / NCI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
U10 CA180886 / CA / NCI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
U01 GM092666 / GM / NIGMS NIH HHS / United States
U01 CA176063 / CA / NCI NIH HHS / United States
U01 GM097119 / GM / NIGMS NIH HHS / United States