Silencing of a Single Gene Associated with Smoking and Lung Cancer

New research from Zdenko Herceg, Ph.D., head of the Epigenetics Group at the International Agency for Research on Cancer (IARC) shows how tobacco smoking leads to lung cancer.

The researchers discovered that a process known as methylation modifies the behavior of genes. According to Dr. Herceg, "We found that tobacco-mediated hypermethylation of MTHFR, and consequent partial or complete silencing of the gene, may trigger global hypomethylation and deregulation of DNA synthesis, both of which may contribute to cancer development." The process is different from gene mutations that cause disease. Hypomethylation and hypermethylation alter the activity of normal genes. Hypermethylation refers to inactivation of genes, and hypomethylation refers to decreased gene activity. The scientists believe the methylation process becomes imbalanced, changing the chemical structure of our DNA, leading to cancer. Dr. Herceg says, the process has not been well defined.

Herceg further explains, "While there is evidence that the mutations induced by these tobacco carcinogens do play an important role in cancer development, our study reveals the novel - and surprising - role that silencing of normal genes plays in development of lung cancer."

The lung cancer study included researchers from Russia, Canada, and the United States, taking tumor samples from 209 lung cancer patients, and blood samples from 172 healthy volunteers, to examine the methylation process. In addition, they examined non-cancerous lung tissue from 51 of the lung cancer patients. The researchers looked at five genes - CDH1, CDKN2A, GSTP1, MTHFR and RASSF1A. They found a high level of hypermethylation in the MTHFR, RASSF1A and CDKN2A genes in lung cancer, but not so with the other two genes. Methylation levels of CDH1, CDKN2A, GSTP1 and RASSF1A were not associated with smoking.

The researchers then determined that silencing of the MTHFR gene most likely contributes to lung cancer development, an important gene already associated with cancer. Dr. Herceg says, "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."

The research provides a better understanding of the role of epigenetics (how genes express themselves) and the development of lung cancer. The findings could lead to the development of a blood or sputum test for lung cancer that uses a “methylation signature” to identify those at high risk, including people exposed to passive smoking. Early diagnosis and treatment would greatly improve the chances of surviving lung cancer.

Source: In Lung Cancer, Silencing One Crucial Gene Disrupts Normal Functioning of Genome