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

Heng Xu; Hui Zhang; Wenjian Yang; Rachita Yadav; Alanna C Morrison; Maoxiang Qian; Meenakshi Devidas; Yu Liu; Virginia Perez-Andreu; Xujie Zhao; Julie M Gastier-Foster; Philip J Lupo; Geoff Neale; Elizabeth Raetz; Eric Larsen; W Paul Bowman; William L Carroll; Naomi Winick; Richard Williams; Torben Hansen; Jens-Christian Holm; Elaine Mardis; Robert Fulton; Ching-Hon Pui; Jinghui Zhang; Charles G Mullighan; William E Evans; Stephen P Hunger; Ramneek Gupta; K. Schmiegelow; Mignon L Loh; Mary V Relling; Jun J Yang

doi:10.1038/ncomms8553

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

Heng Xu, Hui Zhang, Wenjian Yang, Rachita Yadav, Alanna C Morrison, Maoxiang Qian, Meenakshi Devidas, Yu Liu, Virginia Perez-Andreu, Xujie Zhao, Julie M Gastier-Foster, Philip J Lupo, Geoff Neale, Elizabeth Raetz, Eric Larsen, W Paul Bowman, William L Carroll, Naomi Winick, Richard Williams, Torben HansenJens-Christian Holm, Elaine Mardis, Robert Fulton, Ching-Hon Pui, Jinghui Zhang, Charles G Mullighan, William E Evans, Stephen P Hunger, Ramneek Gupta, K. Schmiegelow, Mignon L Loh, Mary V Relling, Jun J Yang

Department of Clinical Medicine

40 Citations (Scopus)

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.

Original language	English
Article number	7553
Journal	Nature Communications
Volume	6
Pages (from-to)	1-7
Number of pages	7
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms8553
Publication status	Published - 24 Jun 2015

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Xu, H., Zhang, H., Yang, W., Yadav, R., Morrison, A. C., Qian, M., Devidas, M., Liu, Y., Perez-Andreu, V., Zhao, X., Gastier-Foster, J. M., Lupo, P. J., Neale, G., Raetz, E., Larsen, E., Bowman, W. P., Carroll, W. L., Winick, N., Williams, R., ... Yang, J. J. (2015). Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Nature Communications, 6, 1-7. [7553]. https://doi.org/10.1038/ncomms8553

Xu, 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, Bowman, WP, 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 & Yang, JJ 2015, 'Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children', Nature Communications, vol. 6, 7553, pp. 1-7. https://doi.org/10.1038/ncomms8553

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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 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.",

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 Jens-Christian Holm and Elaine Mardis and Robert Fulton and Ching-Hon Pui and Jinghui Zhang and Mullighan, {Charles G} and Evans, {William E} and Hunger, {Stephen P} and Ramneek Gupta and K. Schmiegelow and Loh, {Mignon L} and Relling, {Mary V} and Yang, {Jun J}",

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AU - Xu, Heng

AU - Zhang, Hui

AU - Yang, Wenjian

AU - Yadav, Rachita

AU - Morrison, Alanna C

AU - Qian, Maoxiang

AU - Devidas, Meenakshi

AU - Liu, Yu

AU - Perez-Andreu, Virginia

AU - Zhao, Xujie

AU - Gastier-Foster, Julie M

AU - Lupo, Philip J

AU - Neale, Geoff

AU - Raetz, Elizabeth

AU - Larsen, Eric

AU - Bowman, W Paul

AU - Carroll, William L

AU - Winick, Naomi

AU - Williams, Richard

AU - Hansen, Torben

AU - Holm, Jens-Christian

AU - Mardis, Elaine

AU - Fulton, Robert

AU - Pui, Ching-Hon

AU - Zhang, Jinghui

AU - Mullighan, Charles G

AU - Evans, William E

AU - Hunger, Stephen P

AU - Gupta, Ramneek

AU - Schmiegelow, K.

AU - Loh, Mignon L

AU - Relling, Mary V

AU - Yang, Jun J

PY - 2015/6/24

Y1 - 2015/6/24

N2 - 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 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.

AB - 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 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.

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JO - Nature Communications

JF - Nature Communications

M1 - 7553

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

Abstract

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