Analysis of p16 gene mutations and deletions in childhood acute lymphoblastic leukemias

Abstract

PARTICIPANTS:Fifty-six children with ALL (mean age 4 years). Forty (71.43%) had B-cell and 12 (21.43%) had T-cell ALL; 4 (7.1%) were biphenotypic.SAMPLE: DNA samples were extracted from bone marrow upon diagnosis and/or relapse. In 2 T-cell cases, DNA from cerebrospinal fluid (CSF) was analyzed. MAIN MEASUREMENTS:Deletions or nucleotide substitutions in exons 1, 2 and 3 of the p16 gene were determined by PCR and nucleotide sequencing. Event-free survival was determined by the Kaplan-Meyer and log-rank test for patients carrying normal and altered p16. RESULTS:Deletions in exon 3 were observed in five cases. Abnormal migration in PCR was observed in seven cases for exon 1, six for exon 2, and five for exon 3. Mutations in exon 1 were confirmed by direct DNA sequencing in four cases and in exon 2 in two cases. The Kaplan-Meyer survival curves and the log-rank test showed no significant differences in 5-year EFS between children with normal or altered p16, or between patients with B-ALL carrying normal or altered p16 gene. Patients with T-ALL could not be evaluated via Kaplan-Meier due to the small number of cases. CONCLUSIONS:Our results, particularly regarding deletion frequency, agree with others suggesting that deletions in the p16 are initial events in leukemia genesis. The small number of samples did not allow stablishment of correlation between childhood ALL and the p16 point mutations found in our study. Kaplan-Meier analysis revealed no significant correlation between EFS and alterations in ALL. The p16 alterations frequency observed for B and T-ALL agreed with reports from other centers.

CDKN2A and CDKN2B Gene Variants in Acute Lymphoblastic Leukemia in Tunisian Population

“…This prompts the speculation as to possible diagnostic capacity of this variant, given that increased liver enzyme are likely due to hepatic injury from leukemic infiltrates or treatment toxicity [41]. Our data also established correlation between CDKN2A rs3731249 and LAL-B/LAL-T phenotype, with CDKN2A/2B polymorphisms being more correlated with LAL-T than LAL-B [42][43][44][45][46][47].…”

CDKN2A/BAlterations Impair Prognosis in AdultBCR-ABL1–Positive Acute Lymphoblastic Leukemia Patients

“…It is well know that in addition to deletions, the CDKN2A/B locus can also be inactivated by epigenetic silencing through DNA methylation or by point mutations. Methylation of CDKN2A and CDKN2B seems to lack prognostic significance in ALL (26), and the rate of point mutations has been extremely low in ALL (31). In line with these findings, ARF, CDKN2A, and CDKN2B point mutations were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A (D146N).…”

A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups

“…[14][15][16][17][18][19] Although mutations in exons 1 and 2 of CDKN2A have been described in childhood ALL, their incidence appears to be low, ranging from 0% to 7%. 12,[20][21][22][23][24] As reported data on CDKN2A alterations in childhood ALL are discrepant, it remains important to reveal the role of this gene in cancer development. In this study, we have used mutation and methylation analyses as well as genomic technologies to elucidate the principal mode of CDKN2A inactivation in childhood ALL.…”