Tobacco Smoke Triggers Lung Cancer by Disturbing Gene Methylation Patterns

Results of a recent study have helped fill in the blanks in our understanding of how tobacco smoke deactivates tumor suppressor genes and triggers development of lung cancer.

Investigators at the International Agency for Research on Cancer (Lyon, France) applied quantitative profiling of DNA methylation states to a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A) in tumor samples from 209 lung cancer patients and in blood samples from 172 matched normal individuals. Noncancerous lung tissue was also examined from 51 of the lung cancer patients.

Results published in the January 1, 2009, issue of the journal Cancer Research revealed a high frequency of aberrant hypermethylation (which shuts down gene expression) of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed. These findings were consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Tobacco smoking, patient's gender, and alcohol intake strongly influenced the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. The results indicated a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking. Methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targeted specific genes for hypermethylation. Methylation levels in RASSF1A, but not the other genes under study, were influenced by gender, with males showing higher levels of methylation.

"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,” said senior author Dr. Zdenko Herceg, head of the epigenetics group at the International Agency for Research on Cancer. "Tobacco smoke contains many carcinogens, most of which are believed to cause genome damage. 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.”

Related Links:
International Agency for Research on Cancer