Dataset Information

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

ABSTRACT:

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

SUBMITTER: Li C

PROVIDER: S-EPMC8694244 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundGenetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors.MethodsLong-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided.ResultsSurvivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F(2,172) = 4.07, P = .019) and motor skills (monoamine oxidase A, F(2,125) = 5.25, P = .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165) = 3.48, P = .033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135) = 3.8, P = .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158) = 3.95, P = .021; MTHFD1rs1950902, F(2,154) = 5.55, P = .005) and glucocorticoid regulation (vitamin D receptor, F(2,158) = 3.29, P = .039; FKBP prolyl isomerase 5, F(2,154) = 5.6, P = .005). Additionally, MTHFD1rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P < .05; family wise error corrected).ConclusionsResults extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.