The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia.

Chunjie Li, Xinying Zhao, Yingyi He, Ziping Li, Jiabi Qian, Li Zhang, Qian Ye, Fei Qiu, Peng Lian, Maoxiang Qian, Hui Zhang

Pharmacogenetics and genomics 2022 Feb 01

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Genetic 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. We 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. We 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. These 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. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Citation

Chunjie Li, Xinying Zhao, Yingyi He, Ziping Li, Jiabi Qian, Li Zhang, Qian Ye, Fei Qiu, Peng Lian, Maoxiang Qian, Hui Zhang. The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. Pharmacogenetics and genomics. 2022 Feb 01;32(2):43-50