Concordant methylation of the ER and N33 genes in glioblastoma multiforme

Li, Qing; Jedlicka, Anne; Ahuja, Nita; Gibbons, Michael; Baylin, Stephen B.; Burger, Peter C.; Issa, Jean–Pierre J.

doi:10.1038/sj.onc.1201831

Cited by 71 publications

(36 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…THBS1 methylation did not correlate with age, gender or overall survival in this small series. In a previous study (Li et al, 1998), we have described frequent and concordant ER and N33 methylation in GBMs. ER and N33 methylation data was available for 34 cases.…”

Section: Thbs1 Methylation In Gbmmentioning

confidence: 68%

Methylation and silencing of the Thrombospondin-1 promoter in human cancer

et al. 1999

Self Cite

View full text Add to dashboard Cite

Neovascularization is a common feature of many human cancers, but relatively few molecular defects have been demonstrated in genes regulating angiogenesis. Decreased expression of Thrombospondin-1 (THBS1), a P53 and Rb regulated angiogenesis inhibitor, has been observed in some human tumors, including glioblastoma multiforme (GBM). To study whether methylationassociated inactivation is involved in down-regulating THBS1 expression in cancer, we analysed the methylation status of THBS1 in several cell lines and primary tumors. Three cell lines (RKO, CEM and RAJI) were completely methylated at several CpG sites within the THBS1 5' CpG island, and had no detectable expression by RT ± PCR. THBS1 expression was readily reactivated using the methylation-inhibitor 5-deoxy-azacytidine in all three lines. Furthermore, THBS1 methylation was present in 33% (14/42) of primary GBMs. Thus, de novo methylation may serve as a potential way to inactivate THBS1 expression in human neoplasms.

show abstract

Section: Thbs1 Methylation In Gbmmentioning

confidence: 68%

Methylation and silencing of the Thrombospondin-1 promoter in human cancer

et al. 1999

Self Cite

View full text Add to dashboard Cite

show abstract

“…Promoter-associated CpG islands can be chemically modified by methylation of cytosine that prevents expression of the gene. This could be of particular relevance in breast cancer as oestrogen receptor genes may also become hypermethylated (Issa et al, 1997;Li et al, 1998), a potential mechanism for resistance of oestrogen receptor positive breast cancers to endocrine therapy, and gene methylation of the oesotrogen receptor increases with age (Li et al, 1998), as does breast cancer. Thus, altering the methylation status of cancer cells through pharmacological inhibition of DNA methyltransferase with resultant DNA demethylation (Issa et al, 1997) offers a novel therapeutic approach to reactivating tumour suppressor function of genes such as HIC-1, as we have demonstrated here with MDAMB231, but may also be relevant to reactivating the function of what are currently therapeutically useful genes such as oestrogen receptor.…”

Section: Discussionmentioning

confidence: 99%

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

et al. 2001

View full text Add to dashboard Cite

Summary A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2′-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

show abstract

“…In glioblastomas, for instance, frequent promoter hypermethylation has been noted for p14 arf and RB1 (Costello et al, 1996;Watanabe et al, 2002;Gonzalez-Gomez et al, 2003a, b). Most approaches to evaluating methylation as a means of tumor-suppressor gene inactivation in glioblastomas have focused on individual candidate genes (Li et al, 1998(Li et al, , 1999Fan et al, 2002;Watanabe et al, 2002;Dallol et al, 2003;Gonzalez-Gomez et al, 2003a, b;Dickinson et al, 2004;Stone et al, 2004). Although such studies have implicated methylation as a tumorigenic event in human gliomas, these approaches do not provide a means to identify novel genes not considered a priori to be candidates.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of RUNX3 and TES by hypermethylation in glioblastoma

et al. 2006

View full text Add to dashboard Cite

Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Duplicates of three short-term cultured glioblastomas were exposed to 5 lM 5-aza-dC for 96 h followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, reverse transcription-polymerase chain reaction (RT-PCR), bisulfite sequencing, methylationspecific PCR and matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor-suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis.

show abstract

Concordant methylation of the ER and N33 genes in glioblastoma multiforme

Cited by 71 publications

References 13 publications

Methylation and silencing of the Thrombospondin-1 promoter in human cancer

Methylation and silencing of the Thrombospondin-1 promoter in human cancer

Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer

Downregulation of RUNX3 and TES by hypermethylation in glioblastoma

Contact Info

Product

Resources

About