Cancer is often characterized by an imbalance in methylation, where hypermethylation (inactivation) in specific genes is accompanied by hypomethylation (a decrease in methylation in general) across many genes. But this process has not been well characterized, Herceg said.
In this study, researchers from IARC working with investigators from Russia, Canada, and the United States, quantified methylation patterns in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR and RASSF1A) in tumor samples from 209 lung patients and in blood samples from 172 matched "healthy" volunteers.
Noncancerous lung tissue was also examined from 51 of the lung cancer patients.
Their analysis revealed that a high frequency of hypermethylation of MTHFR, RASSF1A and CDKN2A in lung tumors compared to control blood samples, but no significant increase in methylation levels of the other two genes.
Silencing of the RASSF1A and CDKN2A genes makes sense, said Herceg, because these are tumor suppressor genes known to be inactivated in lung cancer. But the role of MTHFR has been less clear, he said. The enzyme produced by the gene plays a role in processing amino acids into methionine, which the body uses to make proteins and other crucial molecules. Variants of MTHFR, for example, have been linked to increased risk of cardiovascular disease.
"Because the MTHFR gene product plays a role in the maintenance of the cell's pool of methionine, silencing of MTHFR is likely to contribute to global hypomethylation, a phenomenon almost universally observed in human cancer that has been overlooked in favor of gene promoter-associated hypermethylation," Herceg said.
Both global hypomethylation and hypermethylation "coexist in all tumors and can contribute to tumor development and progression through different mechanisms," he said. The researchers say that these two
|Contact: Jeremy Moore|
American Association for Cancer Research