Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors.
Current evidence suggests that epigenetic changes play an important role in the evolution of human cancers. In this study, we evaluated whether hypermethylation of CpG islands at the gene promotor regions of several tumor-related genes is involved in the carcinogenesis of oligodendroglial tumors. We examined the methylation status of 11 genes in a series of 43 oligodendroglial tumors (19 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 9 oligoastrocytomas, and 2 anaplastic oligoastrocytomas) by methylation-specific polymerase chain reaction. Our results showed that hypermethylation of CpG islands was detectable in 8 of 11 genes studied and 74% of tumors were hypermethylated in at least 1 gene. Promotor hypermethylations were detected in O6-methylguanine-DNA methyltransferase (MGMT), RB1, estrogen receptor, p73, p16INK4a, death-associated protein kinase, p15INK4b, and p14ARF at 60%, 34%, 30%, 16%, 12%, 10%, 7%, and 2%, respectively. No hypermethylation was detected in the promotors of glutathione-S-transferase P1, von Hippel-Lindau or the DNA mismatch repair (hMLH1) genes. Statistical analysis revealed that concordant hypermethylation of at least 2 genes, p16INK4a and p15INK4b were significantly associated with anaplastic oligodendroglial tumors, and hypermethylation of MGMT was significantly associated with loss of chromosome 19q and with combined loss of chromosomes 1p and 19q. More importantly, several candidate tumor suppressor genes such as p16INK4a, p15INK4b, and p73 that were previously reported as unmutated in oligodendroglial tumors were found to be hypermethylated in their CpG islands. Taken together, we conclude that hypermethylation of CpG islands is a common epigenetic event that is associated with the development of oligodendroglial tumors.
Dong
S M
SM
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong.
Pang
J C
JC
Poon
W S
WS
Hu
J
J
To
K F
KF
Chang
A R
AR
Ng
H K
HK
D001254:Astrocytoma / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D009837:Oligodendroglioma / Q000235:genetics*
D019853:O(6)-Methylguanine-DNA Methyltransferase