p14ARF deletion and methylation in genetic pathways to glioblastomas

International Agency for Research on Cancer, Lyon, France.
Brain Pathology (Impact Factor: 3.84). 05/2001; 11(2):159-68.
Source: PubMed


The CDKN2A locus on chromosome 9p21 contains the p14ARF and p16INK4a genes, and is frequently deleted in human neoplasms, including brain tumors. In this study, we screened 34 primary (de novo) glioblastomas and 16 secondary glioblastomas that had progressed from low-grade diffuse astrocytomas for alterations of the p14ARF and p16INK4a genes, including homozygous deletion by differential PCR, promoter hypermethylation by methylation-specific PCR, and protein expression by immunohistochemistry. A total of 29 glioblastomas (58%) had a p14ARF homozygous deletion or methylation, and 17 (34%) showed p16INK4a homozygous deletion or methylation. Thirteen glioblastomas showed both p14ARF and p16INK4a homozygous deletion, while nine showed only a p14ARF deletion. Immunohistochemistry revealed loss of p14ARF expression in the majority of glioblastomas (38/50, 76%), and this correlated with the gene status, i.e. homozygous deletion or promoter hypermethylation. There was no significant difference in the overall frequency of p14ARF and p16INK4a alterations between primary and secondary glioblastomas. The analysis of multiple biopsies from the same patients revealed hypermethylation of p14ARF (5/15 cases) and p16INK4a (1/15 cases) already at the stage of low-grade diffuse astrocytoma but consistent absence of homozygous deletions. These results suggest that aberrant p14ARF expression due to homozygous deletion or promoter hypermethylation is associated with the evolution of both primary and secondary glioblastomas, and that p14ARF promoter methylation is an early event in subset of astrocytomas that undergo malignant progression to secondary glioblastoma.

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    • "This characteristic pattern has been associated with increased genetic instability, silencing of tumor suppressors such as TP53 and PTEN, and activation of oncogenes. Hypermethylation mostly occurs at the promoter CpG island of genes that are associated with tumor suppression,81,82 DNA repair,83 cell-cycle regulation,84 apoptosis,85,86 invasion,87,88 and migration.89 Interestingly, the methylation patterns differ between gliomas of WHO grade II–IV.90 "
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    • "In silico analysis has suggested association of FBI-1 with gliomas (Rovin and Winn, 2005). LRF represses transcription of the tumor suppressor p14/ARF in humans, and inactivation of p14/ARF is often observed in glioblastoma multiforme (Nakamura et al., 2001). These findings confirm that LRF functions as an oncogene in CNS tumors derived from immature cell types. "
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