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

Year: 2015

Type: article

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.

Source: Nature Communications

DOI: 10.1038/ncomms8553

Institutions: St. Jude Children's Research Hospital, Sichuan University, West China Hospital of Sichuan University, State Key Laboratory of Biotherapy, First Affiliated Hospital of Guangzhou Medical University, Technical University of Denmark, The University of Texas Health Science Center at Houston, University of Florida Health, University of Florida, Nationwide Children's Hospital, The Ohio State University, Baylor College of Medicine, University of Utah, Huntsman Cancer Institute, Cook Children's Medical Center, New York University, The University of Texas Southwestern Medical Center, Puma Biotechnology (United States), University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen University Hospital, Holbæk Sygehus, Washington University in St. Louis, Children's Hospital of Philadelphia, Rigshospitalet, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center

Language: English

Topic: Acute Lymphoblastic Leukemia research

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $6,990

Funders: American Society of Hematology, Strategiske Forskningsråd, Børnecancerfonden, American Lebanese Syrian Associated Charities, National Research Foundation, Danmarks Grundforskningsfond, Danmarks Tekniske Universitet, Barncancerfonden, Region Sjælland, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences

Awards: G1052397333, G1104154511, G1135917780, G1243299691, G1460387277, G1504112592, G1527150935, G1600560672, G1691174148, G173303992, G1772308789, G1941623656, G2510593890, G2688579988, G2818629771, G2901481919, G301743239, G3114902838, G3152385821, G339263803, G3410686264, Pharmacogenomics of Childhood Leukemia ALL, G3462919067, G3503792436, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G386607036, G4167445418, G4200864717, G421865639, G457330776, G46020690, G5053595415, G5066293200, G5074086979, G5075990039, G5668335881, G567847597, G5737582129, G5888954722, G6195637971, G6548750934, G6552090923, G6626909389, G740377980, Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), G865138149, G9000048645, G9000079770, G9000086855, G9000211056, G9000216687, G9000255358, G9000285815, G9000343340, G9000351236, Cancer Center Support Grant (CCSG), G997771125

OpenAlex ID: W2260838386