Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells

Nguyen, Carvell T.; Liang, Gangning; Nguyen, Tu Dung T.; Tsao‐Wei, Denice; Groshen, Susan; Lübbert, Michael; Zhou, Jain; Benedict, William F.; Jones, Peter A.

doi:10.1093/jnci/93.19.1465

Cited by 131 publications

(85 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Methylation of p15 was associated with relapsed ALL patients (Garcia-Manero et al, 2002a), suggesting it might be a late event in the progression of ALL. In AML patients, methylation of p15 gene was demonstrated in 45% of patients which was within the range of previous reports (32-93%) (Melki et al, 1999;Guo et al, 2000;Wong et al, 2000;Wu et al, 2000;Chim et al, 2001;Dodge et al, 2001;Nguyen et al, 2001;Chim et al, 2003;Christiansen et al, 2003;Ekmekci et al, 2004;Galm et al, 2005;Olesen et al, 2005;Shimamoto et al, 2005;El-Shakankiry and Mossallam, 2006;Griffiths et al, 2010;Kurtovic et al, 2012). Previously, low RNA levels of p15 were reported in AML (Schwaller et al, 1997) which was also correlated with methylation of this gene (Matsuno et al, 2005).…”

Section: Discussionsupporting

confidence: 88%

“…In CLL patients, methylation of p15 was observed in 19% of subjects. Previous studies reported 9-36% methylation in p15 (Nguyen et al, 2001;Chim et al, 2006a;Seeliger et al, 2009). In the present study, methylation in p15 gene was seen in all types of leukemia, however it was most frequent in AML (45% of cases).…”

Section: Discussionsupporting

confidence: 50%

“…In CLL patients, methylation was reported in p15 (Nguyen et al, 2001;Chim et al, 2006;Seeliger et al, 2009), p16 (Nosaka et al, 2000;Chim et al, 2006a;Tsirigotis et al, 2006;Seeliger et al, 2009) and DAPK (Katzenellenbogen et al, 1999;Chim et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 50%

See 1 more Smart Citation

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

show abstract

“…This is in line with the hypothesis that exonic CpG islands are most susceptible for de novo methylation. 26 Thus, hypermethylation of the paternal allele might initiate in CpG island III and then spread to CpG island I near the promoter region (Fig. 1b).…”

Section: Discussionmentioning

confidence: 99%

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Riemenschneider

Reifenberger

2008

Intl Journal of Cancer

View full text Add to dashboard Cite

Deletion of the short arm of chromosome 1 is common in oligodendroglial tumors and has been identified as a powerful molecular marker for response to radio-and chemotherapy as well as favorable prognosis. Here, we investigated a series of 59 human primary gliomas for aberrations of the DIRAS3 (ARHI) gene, a maternally imprinted RAS-related tumor suppressor at 1p31. We found that DIRAS3 mRNA expression levels were significantly decreased in oligodendrogliomas with 1p deletion when compared to tumors with retention on 1p. While mutational analysis yielded no tumor-associated mutations, assessment of the methylation status of DIRAS3 showed biallelic DIRAS3 inactivation due to methylation of the retained allele in 95% of oligodendrogliomas (19 out of 20) with 1p deletions. In contrast, only 28% of oligodendrogliomas (5 out of 18) without 1p deletions and less than 5% of astrocytic tumors (1 out 21) had biallelic inactivation, i.e., methylation of both DIRAS3 alleles. Furthermore, in oligodendroglioma patients biallelic DIRAS3 inactivation was significantly associated with low DIRAS3 transcripts levels and longer overall survival. Taken together, our data suggest DIRAS3 as a novel, prognostically relevant candidate gene that is frequently methylated and silenced in oligodendroglial tumors with 1p deletion. ' 2008 Wiley-Liss, Inc.Key words: DIRAS3; ARHI; oligodendroglioma; 1p; methylation The DIRAS3 gene at 1p31 encodes a small 26 kDa GTPase with 60% homology to Ras and Rap. 1 Despite its affiliation to the RAS superfamily DIRAS3 exhibits characteristics of a tumor suppressor gene. In breast cancer cell lines the expression of DIRAS3 suppresses clonogenic growth, reduces invasiveness and induces apoptosis. 2 The downstream mechanisms conveying these tumor suppressor functions of DIRAS3 have not yet been fully understood. Inhibition of signalling through RAS/MAPK, PI3K and STAT3 pathways, downregulation of cyclin D1, upregulation of p21(WAF1/CIP1) as well as induction of JNK and caspase-independent, calpain-dependent apoptosis have all been attributed to mediate DIRAS3 downstream signaling effects. [2][3][4][5] DIRAS3 is one of about 40 known imprinted genes within the genome. In human tissues, it is solely expressed from the paternal allele, while the maternal copy is silenced early in embryonal development. 1 The gene comprises 2 exons with the entire 229-base pair coding region located in exon 2. Three potential CpG islands have been attributed to DIRAS3. CpG island I is located about 1 kb upstream of the transcription start site, CpG island II spans both the transcription start site and a portion of exon 1 and CpG island III is located within the protein coding region of exon 2. 6 A study on breast cancer cells suggested CpG island II as the functionally most relevant site for epigenetic inactivation. 7 DIRAS3 maps to 1p31, a chromosomal region that often exhibits loss of heterozygosity in oligodendroglial tumors of the brain. 8 In oligodendrogliomas, determination of the 1p deletion status has attracted particula...

show abstract

“…However, the results were probably influenced by the use of the CpG methylation-sensitive NotI for the DNA digestion because NotI preferentially cleaves in CpG-rich regions of the mammalian genome. Cancer-associated hypermethylation is seen in CpG islands distant from the 5' end of the gene Nguyen et al, 2001a) as well as in those that straddle the transcription start site. Therefore, the observed prevalence of cancer-linked hypermethylation in 5' CpG islands may be due to an ascertainment bias.…”

Section: Types Of Sequences Affected By Cancer-associated Hypermethylmentioning

confidence: 99%

DNA methylation in cancer: too much, but also too little

2002

View full text Add to dashboard Cite

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

show abstract

Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells

Cited by 131 publications

References 20 publications

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

DNA methylation in cancer: too much, but also too little

Contact Info

Product

Resources

About