Among grade IV glioblastoma patients, the median survival for the CIMP-positive group was 150 weeks, compared with 42 weeks for those negative for this epigenetic alteration. CIMP-positivity was more common in low- and intermediate-grade tumors, with a 10-fold increase in methylation seen in grade II tumors compared with grade IV glioblastomas.
Aldape said study results could lead to better therapies two ways. "First, this alteration could identify glioblastoma patients with outcomes similar to lower grade tumors. Second, since it is so common in lower grade tumors, it represents a new therapeutic target for these patients."
Methylation also was tightly associated with mutation in the IDHI gene in 78 percent of cases. IDHI mutations were recently associated with lower grade gliomas.
The researchers note that a subset of grade IV glioblastoma patients tends to be younger and have a relatively favorable prognosis. These patients might be identified in advance by using biomarkers such as CpG island methylation and IDH1 gene mutations. By the same token, the markers could be used to identify patients with low- or intermediate grade gliomas who may have relatively unfavorable prospects for their tumor grade.
They also found that of the 1,520 genes with promoter hypermethylation, only 293 genes, or 19 percent, showed a decrease in expression. "Epigenetics controls expression potential (of genes), rather than expression state," the authors noted.
Hypermethylation might promote tumor development by silencing two tumor-suppressing genes, the team reported, or by silencing others to provide a favorable context for genetic damage to occur.
The 27 co-authors on the project are from eight academic institutions and one biotechnology company. "Complex problems, such as defining clinically relevant molecular changes in human cancer, require cooperation among many individuals with complementary expertise and therefore require a 'team science' approach," Aldape said.
Source: University of Texas M. D. Anderson Cancer Center