Frequency variations in the methylated pattern of p73/p21 genes and chromosomal aberrations correlating with different grades of glioma among south Indian population

Abstract

Gliomas are the most common primary brain tumors in India. The main epigenetic modification in glioma is aberrant DNA methylation that is now renowned to be a common hallmark of brain tumors. This study was designed to determine the frequency of aberrant CpG island methylation in the promoter regions of p21 and p73 in different grades of glioma and to explore their respective chromosomal aberrations. Total of 160 patients with histologically confirmed grades of glioma (I, II, III, and IV) were included in the study. DNA samples from blood and brain tissues, including benign lesions were subjected to sodium bisulfite conversion and hypermethylation detection using methylation-specific PCR followed by RT-PCR. Western blotting was also carried out for p21 and its related protein, p53. A total of 124 of 160 glioma samples (77.5%) displayed CpG island hypermethylation of both p73, p21 genes associated with the loss of mRNA expression (P < 0.001) and the loss of protein expressions (p53 independent p21 expression). p73 gene showed increased methylation frequency in all grades, 40 of 60 (66%) glioblastomas and 16 of 30 (53.3%) anaplastic astrocytoma, 10 of 20(50%) oligodendrogliomas, 8 of 20 (40%) ependymoma, and low-grade glioma 6 of 20 (30%). The percentage of methylation significantly well correlated with the overall survival and also with chromosomal loss. Thus, the studied glioma patients among south Indians showed a high frequency of aberrant methylation with varied chromosomal signatures in different grades, playing a role in aggressiveness and characterization of a particular grade, the appreciation of which might help for designing a specific therapy.

The p53 Pathway in Glioblastoma

“…Therefore, downregulation of TP63 and TP73 may also contribute to the malignancy and treatment resistance of GBM [ 102 , 103 ]. Indeed, methylation of the promoter regions of TP63 and TP73 corresponded with higher grade GBM [ 104 ]. As GOF mut-p53 have been demonstrated to negatively regulate p63 and p73 activity, mut-p53 might be involved in the GSC’s resistance to differentiation and enhanced capacity for invasion [ 72 , 101 ].…”

Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro

“…Inactivation of RASSF1A due to aberrant hypermethylation within promoter region is a frequent event in lung cancer patients (Fujiwara et al, 2005; Hsu et al, 2007). Promoter hypermethylation of p53 has been observed in individuals with leukemia (Agirre et al, 2003a; Agirre et al, 2003b; Martinez-Delgado et al, 2002), lung (Woodson et al, 2001) and brain tumors (Palani et al, 2010). Exposure to Arsenic, which has been used as pesticide, was associated with hypermethylation at the promoter region of RASSF1A and p53 both in vitro and in vivo (Ren et al, 2011).…”