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

E.A. Hungate; S.R. Vora; E.R. Gamazon; T. Moriyama; T. Best; I. Hulur; Y. Lee; T.J. Evans; E. Ellinghaus; M. Stanulla; J. Rudant; L. Orsi; J. Clavel; Elizabeth Milne; R.J. Scott; C.H. Pui; N.J. Cox; M.L. Loh; J.J. Yang; A.D. Skol; K. Onel

doi:10.1038/ncomms10635

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

E.A. Hungate, S.R. Vora, E.R. Gamazon, T. Moriyama, T. Best, I. Hulur, Y. Lee, T.J. Evans, E. Ellinghaus, M. Stanulla, J. Rudant, L. Orsi, J. Clavel, Elizabeth Milne, R.J. Scott, C.H. Pui, N.J. Cox, M.L. Loh, J.J. Yang, A.D. Skol & 1 others K. Onel

Centre for Child Health Research

Research output: Contribution to journal › Article

23 Citations (Scopus)

Abstract

© 2016, Nature Publishing Group. All rights reserved. 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 (Pcombined=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.

Original language	English
Pages (from-to)	10635
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10635
Publication status	Published - 2016

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Hungate, E. A., Vora, S. R., Gamazon, E. R., Moriyama, T., Best, T., Hulur, I., ... Onel, K. (2016). A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. Nature Communications, 7, 10635. https://doi.org/10.1038/ncomms10635

Hungate, E.A. ; Vora, S.R. ; Gamazon, E.R. ; Moriyama, T. ; Best, T. ; Hulur, I. ; Lee, Y. ; Evans, T.J. ; Ellinghaus, E. ; Stanulla, M. ; Rudant, J. ; Orsi, L. ; Clavel, J. ; Milne, Elizabeth ; Scott, R.J. ; Pui, C.H. ; Cox, N.J. ; Loh, M.L. ; Yang, J.J. ; Skol, A.D. ; Onel, K. / A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. In: Nature Communications. 2016 ; Vol. 7. pp. 10635.

@article{6d0dc5dc91ae4d0889e5a34bb7a9a891,

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

abstract = "{\circledC} 2016, Nature Publishing Group. All rights reserved. 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 (Pcombined=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.",

author = "E.A. Hungate and S.R. Vora and E.R. Gamazon and T. Moriyama and T. Best and I. Hulur and Y. Lee and T.J. Evans and E. Ellinghaus and M. Stanulla and J. Rudant and L. Orsi and J. Clavel and Elizabeth Milne and R.J. Scott and C.H. Pui and N.J. Cox and M.L. Loh and J.J. Yang and A.D. Skol and K. Onel",

year = "2016",

doi = "10.1038/ncomms10635",

language = "English",

volume = "7",

pages = "10635",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

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Hungate, EA, Vora, SR, Gamazon, ER, Moriyama, T, Best, T, Hulur, I, Lee, Y, Evans, TJ, Ellinghaus, E, Stanulla, M, Rudant, J, Orsi, L, Clavel, J, Milne, E, Scott, RJ, Pui, CH, Cox, NJ, Loh, ML, Yang, JJ, Skol, AD & Onel, K 2016, 'A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology' Nature Communications, vol. 7, pp. 10635. https://doi.org/10.1038/ncomms10635

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. / Hungate, E.A.; Vora, S.R.; Gamazon, E.R.; Moriyama, T.; Best, T.; Hulur, I.; Lee, Y.; Evans, T.J.; Ellinghaus, E.; Stanulla, M.; Rudant, J.; Orsi, L.; Clavel, J.; Milne, Elizabeth; Scott, R.J.; Pui, C.H.; Cox, N.J.; Loh, M.L.; Yang, J.J.; Skol, A.D.; Onel, K.

In: Nature Communications, Vol. 7, 2016, p. 10635.

Research output: Contribution to journal › Article

TY - JOUR

T1 - A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology

AU - Hungate, E.A.

AU - Vora, S.R.

AU - Gamazon, E.R.

AU - Moriyama, T.

AU - Best, T.

AU - Hulur, I.

AU - Lee, Y.

AU - Evans, T.J.

AU - Ellinghaus, E.

AU - Stanulla, M.

AU - Rudant, J.

AU - Orsi, L.

AU - Clavel, J.

AU - Milne, Elizabeth

AU - Scott, R.J.

AU - Pui, C.H.

AU - Cox, N.J.

AU - Loh, M.L.

AU - Yang, J.J.

AU - Skol, A.D.

AU - Onel, K.

PY - 2016

Y1 - 2016

N2 - © 2016, Nature Publishing Group. All rights reserved. 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 (Pcombined=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.

AB - © 2016, Nature Publishing Group. All rights reserved. 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 (Pcombined=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.

U2 - 10.1038/ncomms10635

DO - 10.1038/ncomms10635

M3 - Article

VL - 7

SP - 10635

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -

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