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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 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.

SUBMITTER: Xu H 

PROVIDER: S-EPMC4544058 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Xu Heng H   Zhang Hui H   Yang Wenjian W   Yadav Rachita R   Morrison Alanna C AC   Qian Maoxiang M   Devidas Meenakshi M   Liu Yu Y   Perez-Andreu Virginia V   Zhao Xujie X   Gastier-Foster Julie M JM   Lupo Philip J PJ   Neale Geoff G   Raetz Elizabeth E   Larsen Eric E   Bowman W Paul WP   Carroll William L WL   Winick Naomi N   Williams Richard R   Hansen Torben T   Holm Jens-Christian JC   Mardis Elaine E   Fulton Robert R   Pui Ching-Hon CH   Zhang Jinghui J   Mullighan Charles G CG   Evans William E WE   Hunger Stephen P SP   Gupta Ramneek R   Schmiegelow Kjeld K   Loh Mignon L ML   Relling Mary V MV   Yang Jun J JJ  

Nature communications 20150624


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  ...[more]

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