Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk.
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ABSTRACT:
SUBMITTER: Sherborne AL
PROVIDER: S-EPMC3434228 | biostudies-literature | 2010 Jun
REPOSITORIES: biostudies-literature
Publications
Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk.
Sherborne Amy L AL Hosking Fay J FJ Prasad Rashmi B RB Kumar Rajiv R Koehler Rolf R Vijayakrishnan Jayaram J Papaemmanuil Elli E Bartram Claus R CR Stanulla Martin M Schrappe Martin M Gast Andreas A Dobbins Sara E SE Ma Yussanne Y Sheridan Eamonn E Taylor Malcolm M Kinsey Sally E SE Lightfoot Tracey T Roman Eve E Irving Julie A E JA Allan James M JM Moorman Anthony V AV Harrison Christine J CJ Tomlinson Ian P IP Richards Sue S Zimmermann Martin M Szalai Csaba C Semsei Agnes F AF Erdelyi Daniel J DJ Krajinovic Maja M Sinnett Daniel D Healy Jasmine J Gonzalez Neira Anna A Kawamata Norihiko N Ogawa Seishi S Koeffler H Phillip HP Hemminki Kari K Greaves Mel M Houlston Richard S RS
Nature genetics 20100509 6
Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage. ...[more]
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Project description: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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Project description:ObjectiveGenetic alterations in CDKN2A tumor suppressor gene on chromosome 9p21 confer a predisposition to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified missense variants in CDKN2A associated with the development of ALL. This study systematically evaluated the effects of CDKN2A coding variants on ALL risk.MethodsWe genotyped the CDKN2A coding region in 308 childhood ALL cases enrolled in CCCG-ALL-2015 clinical trials by Sanger Sequencing. Cell growth assay, cell cycle assay, MTT-based cell toxicity assay, and western blot were performed to assess the CDKN2A coding variants on ALL predisposition.ResultsWe identified 10 novel exonic germline variants, including 6 missense mutations (p.A21V, p.G45A and p.V115L of p16INK4A; p.T31R, p.R90G, and p.R129L of p14ARF) and 1 nonsense mutation and 1 heterozygous termination codon mutation in exon 2 (p16INK4A p.S129X). Functional studies indicate that five novel variants resulted in reduced tumor suppressor activity of p16INK4A, and increased the susceptibility to the leukemic transformation of hematopoietic progenitor cells. Compared to other variants, p.H142R contributes higher sensitivity to CDK4/6 inhibitors.ConclusionThese findings provide direct insight into the influence of inherited genetic variants at the CDKN2A coding region on the development of ALL and the precise clinical application of CDK4/6 inhibitors.
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2019-02-25 | PXD010175 | Pride