AustralieFrV1, Main, Exploration, bibRecord, 002432

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

Identifieur interne : 002432 ( Main/Exploration ); précédent : 002431; suivant : 002433

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

Auteurs : Eric A. Hungate [États-Unis] ; Sapana R. Vora [États-Unis] ; Eric R. Gamazon [États-Unis, Pays-Bas] ; Takaya Moriyama [États-Unis] ; Timothy Best [États-Unis] ; Imge Hulur [États-Unis] ; Younghee Lee [États-Unis] ; Tiffany-Jane Evans [Australie] ; Eva Ellinghaus [Allemagne] ; Martin Stanulla [Allemagne] ; Jéremie Rudant [France] ; Laurent Orsi [France] ; Jacqueline Clavel [France] ; Elizabeth Milne [Australie] ; Rodney J. Scott [Australie] ; Ching-Hon Pui [États-Unis] ; Nancy J. Cox [États-Unis] ; Mignon L. Loh [États-Unis] ; Jun J. Yang [États-Unis] ; Andrew D. Skol [États-Unis] ; Kenan Onel [États-Unis]

Source :

Nature Communications [ 2041-1723 ] ; 2016.

RBID : PMC:4754340

Descripteurs français

English descriptors

Abstract

Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (P_combined=3.32 × 10⁻¹⁵, OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754340

DOI: 10.1038/ncomms10635
PubMed: 26868379
PubMed Central: 4754340

Affiliations:

Allemagne, Australie, France, Pays-Bas, États-Unis

Le document en format XML

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<author><name sortKey="Onel, Kenan" sort="Onel, Kenan" uniqKey="Onel K" first="Kenan" last="Onel">Kenan Onel</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Evans, Tiffany Jane" sort="Evans, Tiffany Jane" uniqKey="Evans T" first="Tiffany-Jane" last="Evans">Tiffany-Jane Evans</name>
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, New South Wales 2305,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Ellinghaus, Eva" sort="Ellinghaus, Eva" uniqKey="Ellinghaus E" first="Eva" last="Ellinghaus">Eva Ellinghaus</name>
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, Kiel 24118,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Stanulla, Martin" sort="Stanulla, Martin" uniqKey="Stanulla M" first="Martin" last="Stanulla">Martin Stanulla</name>
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, Kiel 24105,<country>Germany</country>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Rudant, Jeremie" sort="Rudant, Jeremie" uniqKey="Rudant J" first="Jéremie" last="Rudant">Jéremie Rudant</name>
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, Villejuif 94807,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University</institution>
, Paris 75270,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Orsi, Laurent" sort="Orsi, Laurent" uniqKey="Orsi L" first="Laurent" last="Orsi">Laurent Orsi</name>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)</institution>
, Villejuif 94807,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University</institution>
, Paris 75270,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clavel, Jacqueline" sort="Clavel, Jacqueline" uniqKey="Clavel J" first="Jacqueline" last="Clavel">Jacqueline Clavel</name>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>INSERM U1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Epidemiology of Childhood and Adolescent Cancers Team (EPICEA)</institution>
, Villejuif 94807,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>UMRS-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Paris-Descartes University</institution>
, Paris 75270,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a12"><institution>French National Registry of Childhood Hematopoietic Malignancies (RNHE)</institution>
, Villejuif 94807,<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Milne, Elizabeth" sort="Milne, Elizabeth" uniqKey="Milne E" first="Elizabeth" last="Milne">Elizabeth Milne</name>
<affiliation wicri:level="1"><nlm:aff id="a13"><institution>Telethon Kids Institute, University of Western Australia</institution>
, Crawley, Western Australia 6872,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Scott, Rodney J" sort="Scott, Rodney J" uniqKey="Scott R" first="Rodney J." last="Scott">Rodney J. Scott</name>
<affiliation wicri:level="1"><nlm:aff id="a7"><institution>Faculty of Medicine and Health, Information Based Medicine, Hunter Medical Research Institute, School of Biomedical Sciences and Pharmacy, University of Newcastle, New Lambton</institution>
, New South Wales 2305,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a14"><institution>Division of Molecular Medicine, Pathology North, John Hunter Hospital</institution>
, Newcastle, New South Wales 2305,<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pui, Ching Hon" sort="Pui, Ching Hon" uniqKey="Pui C" first="Ching-Hon" last="Pui">Ching-Hon Pui</name>
<affiliation wicri:level="1"><nlm:aff id="a15"><institution>Department of Oncology, St Jude Children's Research Hospital</institution>
, Memphis, Tennessee 38105, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, Memphis, Tennessee 38105</wicri:regionArea>
<wicri:noRegion>Tennessee 38105</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cox, Nancy J" sort="Cox, Nancy J" uniqKey="Cox N" first="Nancy J." last="Cox">Nancy J. Cox</name>
<affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Medicine, Vanderbilt University Medical Center</institution>
, Nashville, Tennessee 37232, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, Nashville, Tennessee 37232</wicri:regionArea>
<wicri:noRegion>Tennessee 37232</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Loh, Mignon L" sort="Loh, Mignon L" uniqKey="Loh M" first="Mignon L." last="Loh">Mignon L. Loh</name>
<affiliation wicri:level="1"><nlm:aff id="a16"><institution>Department of Pediatrics, University of California–San Francisco</institution>
, San Francisco, California 94143, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, San Francisco, California 94143</wicri:regionArea>
<wicri:noRegion>California 94143</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Yang, Jun J" sort="Yang, Jun J" uniqKey="Yang J" first="Jun J." last="Yang">Jun J. Yang</name>
<affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Pharmaceutical Sciences, St Jude Children's Research Hospital</institution>
, Memphis, Tennessee 38105, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, Memphis, Tennessee 38105</wicri:regionArea>
<wicri:noRegion>Tennessee 38105</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Skol, Andrew D" sort="Skol, Andrew D" uniqKey="Skol A" first="Andrew D." last="Skol">Andrew D. Skol</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, University of Chicago</institution>
, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637</wicri:regionArea>
<wicri:noRegion>Illinois 60637</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Onel, Kenan" sort="Onel, Kenan" uniqKey="Onel K" first="Kenan" last="Onel">Kenan Onel</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, University of Chicago</institution>
, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>, 900 East 57th Street, Room 5140, MC 4060, Chicago, Illinois 60637</wicri:regionArea>
<wicri:noRegion>Illinois 60637</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Nature Communications</title>
<idno type="eISSN">2041-1723</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>African Americans (genetics)</term>
<term>Case-Control Studies</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Chromosome Mapping</term>
<term>Chromosomes, Human, Pair 9 (genetics)</term>
<term>Cyclin-Dependent Kinase Inhibitor p15 (genetics)</term>
<term>European Continental Ancestry Group (genetics)</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Variation</term>
<term>Genome-Wide Association Study</term>
<term>Hispanic Americans (genetics)</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Polymorphism, Single Nucleotide</term>
<term>Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Afro-Américains (génétique)</term>
<term>Cartographie chromosomique</term>
<term>Chromosomes humains de la paire 9 (génétique)</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Hispano-américain (génétique)</term>
<term>Humains</term>
<term>Inhibiteur p15 de kinase cycline-dépendante (génétique)</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B (génétique)</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Population d'origine européenne (génétique)</term>
<term>Prédisposition génétique à une maladie</term>
<term>Variation génétique</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cyclin-Dependent Kinase Inhibitor p15</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>African Americans</term>
<term>Chromosomes, Human, Pair 9</term>
<term>European Continental Ancestry Group</term>
<term>Hispanic Americans</term>
<term>Precursor B-Cell Lymphoblastic Leukemia-Lymphoma</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Afro-Américains</term>
<term>Chromosomes humains de la paire 9</term>
<term>Hispano-américain</term>
<term>Inhibiteur p15 de kinase cycline-dépendante</term>
<term>Leucémie-lymphome lymphoblastique à précurseurs B</term>
<term>Population d'origine européenne</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Case-Control Studies</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Chromosome Mapping</term>
<term>Female</term>
<term>Genetic Predisposition to Disease</term>
<term>Genetic Variation</term>
<term>Genome-Wide Association Study</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Polymorphism, Single Nucleotide</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Cartographie chromosomique</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Humains</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Prédisposition génétique à une maladie</term>
<term>Variation génétique</term>
<term>Étude d'association pangénomique</term>
<term>Études cas-témoins</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (<italic>P</italic>
<sub>combined</sub>
=3.32 × 10<sup>−15</sup>
, OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a <italic>cis</italic>
-eQTL for <italic>CDKN2B</italic>
, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating <italic>CDKN2B</italic>
 expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining <italic>CDKN2A</italic>
 exon 3 usage (<italic>P</italic>
=0.01). These findings provide new insights into the critical role of the <italic>CDKN2</italic>
 locus in BCP-ALL aetiology.</p>
</div>
</front>
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</biblStruct>
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   |texte=   A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology
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Serveur d'exploration sur les relations entre la France et l'Australie

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

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