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; Torben Hansen; Jens-Christian Holm; Ramneek Gupta

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, Torben Hansen, Jens-Christian Holm, Ramneek Gupta

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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 x 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
Number of pages	7
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms8553
Publication status	Published - 2015

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.

Keywords

Biological sciences
Cancer
Genetics

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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 x 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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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 - Hansen, Torben

AU - Holm, Jens-Christian

AU - Gupta, Ramneek

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.

PY - 2015

Y1 - 2015

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 x 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 x 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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KW - Cancer

KW - Genetics

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

Abstract

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Keywords

UN SDGs

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