Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia

Guo, Shu-Xia; Taki, Tomohiko; Ohnìshì, H.; Piao, Huiying; Tabuchi, Ken; Bessho, Fumio; Hanada, Ryoji; Yamaguchi, Masayoshi; Hayashi, Yasuhide

doi:10.1016/s0145-2126(99)00158-7

Cited by 103 publications

(62 citation statements)

References 24 publications

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“…In our larger series, this was even more notable in T-ALLs. There is still controversy on the role of these cyclin-dependent kinase inhibitors in lymphoid malignancies, 17,[36][37][38] suggesting that their inactivation may be critical only in a still undetermined molecular subtype of leukemia. For example, it has been reported that p16 methylation is frequent in MLL-leukemias, but we identified only one out of seven such cases.…”

Section: Discussionmentioning

confidence: 99%

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

et al. 2003

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Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O 6 MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O 6 MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI ¼ number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children X10 years old and children presenting with high WBC (X50 Â 10 9 /l) both associated with a higher MI (Po0.01 and o0.05, respectively). T-ALLs demonstrated a lower MI (median ¼ 0.17) than precursor B ALLs (median ¼ 0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean ¼ 0.35), while ALLs carrying the t(1;19) had the lowest MI (mean ¼ 0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

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Section: Discussionmentioning

confidence: 99%

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

et al. 2003

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“…[4][5][6][7][8] In acute lymphoblastic leukemia (ALL), inactivation of the p15 and p16 genes represents one of the most common genetic mechanisms of tumorigenesis. 9 Some authors have suggested that alterations in the p16 gene are associated with a higher frequency of relapse and lower survival in T-cell acute lymphoblastic leukemias both in adults 10 and children. [11][12][13] Therefore, p16 inactivation might be of prognostic value in acute lymphoblastic leukemias, especially T-cell acute lymphoblastic leukemias, playing an important role in its genesis or evolution.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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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.

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“…The p15 INK4b gene was found to be methylated in around 34% of acute lymphoblastic leukemia (ALL), 52% of acute myeloid leukemia (AML), and 18% of chronic myelogenous leukemia (CML) (Guo et al, 2000;Uehara et al, 2012). Alteration of the p15 INK4b gene was also linked to the genetic events in bladder cancer which occurs more frequently in schistosomiasis-associated bladder cancer (SABC) and SCC, and may play an important role in the pathogenesis of SABC.…”

Section: Discussionmentioning

confidence: 99%

Lack of Increased P15^INK4BProtein Expression in Basal Cell Carcinomas

Moad

Tan

Kaur

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia

Cited by 103 publications

References 24 publications

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

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

Lack of Increased P15^INK4BProtein Expression in Basal Cell Carcinomas

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Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia

Cited by 103 publications

References 24 publications

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

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

Lack of Increased P15INK4BProtein Expression in Basal Cell Carcinomas

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Lack of Increased P15^INK4BProtein Expression in Basal Cell Carcinomas