The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A.

Authors:
Jayaram Vijayakrishnan
Jayaram Vijayakrishnan
Institute of Cancer Research
United Kingdom
Marc Henrion
Marc Henrion
National Cancer Institute
United States
Anthony V Moorman
Anthony V Moorman
University of Southampton
United Kingdom
Bettina Fiege
Bettina Fiege
Division of Molecular Genetic Epidemiology
Rajiv Kumar
Rajiv Kumar
German Cancer Research Center
United States
Amy Holroyd
Amy Holroyd
Institute of Cancer Research
United Kingdom
Rolf Koehler
Rolf Koehler
University of Heidelberg
Germany

Sci Rep 2015 Oct 14;5:15065. Epub 2015 Oct 14.

Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio = 2.42, P = 3.45 × 10(-19)). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.

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Source
http://dx.doi.org/10.1038/srep15065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604478PMC

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October 2015
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