The comprehensive mutational and bioinformatics analysis reveals novel somatic mutations in the CDKN2A and CDKN2B genes in pediatric patients with B-cell acute lymphoblastic leukemia (B-All)

Acute lymphoblastic leukemia (ALL) is the most common type of hematological malignancy in children and is characterized by the accumulation of immature lymphoid cells in the bone marrow. Genome-wide association studies have identified genetic variations in the tumor suppressor genes CDKN2A and CDKN2B, which are associated with an increased risk of childhood ALL. These genes encode the proteins p16Ink4A, p14ARF, and p15Ink4B, which are cyclin-dependent kinase inhibitors and interact with CDK4/6 to inhibit the G1/S transition of the cell cycle. To explore genomic variations in the CDKN2A and CDKN2B genes, we conducted mutation screening assays on all four exons of the CDKN2A gene and the coding sequences of the CDKN2B gene. Additionally, we employed various in-silico structural and functional tools to investigate the potential impact of missense mutations. Our analysis identified 15 nucleotide variations in the CDKN2A gene, which encodes the p14ARF and p16INK4A proteins. This included four missense changes and eleven nucleotide alterations in the intronic and untranslated regions. In the CDKN2B gene, we found four missense variations that affect the p15Ink4B protein. Utilizing in-silico analysis, we discovered that three of these missense substitutions Asn39Ile (p16INK4A), Gly47Arg (p15Ink4B), and Cys72Ser (p16INK4A) are predicted to have deleterious and pathogenic effects, which are associated with an increased risk of ALL (P < 0.05). These findings enhance our understanding of how genetic variants in the CDKN2A and CDKN2B genes influence the development of ALL and highlight their potential as tumor biomarkers for managing the disease.