The comprehensive mutational and bioinformatics analysis reveals novel somatic mutations in the CDKN۲A and CDKN۲B 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 CDKN۲A and CDKN۲B, which are associated with an increased risk of childhood ALL. These genes encode the proteins p۱۶Ink۴A, p۱۴ARF, and p۱۵Ink۴B, which are cyclin-dependent kinase inhibitors and interact with CDK۴/۶ to inhibit the G۱/S transition of the cell cycle. To explore genomic variations in the CDKN۲A and CDKN۲B genes, we conducted mutation screening assays on all four exons of the CDKN۲A gene and the coding sequences of the CDKN۲B gene. Additionally, we employed various in-silico structural and functional tools to investigate the potential impact of missense mutations. Our analysis identified ۱۵ nucleotide variations in the CDKN۲A gene, which encodes the p۱۴ARF and p۱۶INK۴A proteins. This included four missense changes and eleven nucleotide alterations in the intronic and untranslated regions. In the CDKN۲B gene, we found four missense variations that affect the p۱۵Ink۴B protein. Utilizing in-silico analysis, we discovered that three of these missense substitutions Asn۳۹Ile (p۱۶INK۴A), Gly۴۷Arg (p۱۵Ink۴B), and Cys۷۲Ser (p۱۶INK۴A) are predicted to have deleterious and pathogenic effects, which are associated with an increased risk of ALL (P < ۰.۰۵). These findings enhance our understanding of how genetic variants in the CDKN۲A and CDKN۲B genes influence the development of ALL and highlight their potential as tumor biomarkers for managing the disease.

کلیدواژه ها:

Cyclin-Dependent Kinase Inhibitors ، Missense Mutations ، Pediatric Leukemia ، Somatic Mutations ، Tumor Biomarkers