ISLAMABAD: New research has revealed how long-term exposure to cigarette smoke may alter lung cells in ways that make them sensitive to genetic triggers for cancer.

In the journal Cancer Cell, scientists from the Johns Hopkins Kimmel Cancer Center in Baltimore, MD, describe how they used cell-level laboratory experiments to map a series of "epigenetic" events that, over time, may connect exposure to cigarette smoke to lung cancer.

Lung cancer is a disease in which abnormal cells in the lungs grow out of control and form tumors. It is the most common cancer worldwide and accounted for 1.8 million of the 14.1 million estimated cancer cases in 2012, which is the latest year for global statistics.

Cigarette smoking is the leading cause of lung cancer and accounts for 85 percent of all types.

In the United States, lung cancer was responsible for 27 percent of all cancer deaths in 2011. However, after rising for decades, rates of lung cancer in the U.S. are now falling, in line with reducing rates of cigarette smoking.

The new study concerns epigenetics - that is, factors apart from our DNA (such as environment) that can alter the way in which our genes behave. For example, epigenetic changes can "switch genes on and off" and decide which proteins are made in cells.

Epigenetic changes take various forms, one of which is methylation - or the chemical addition of tiny methyl groups to the start of a gene's DNA code. This often results in deactivating or "silencing" the gene.In their study paper, the authors explain that scientists now understand cancer to be a "complex process involving both genetic and epigenetic abnormalities" that can be brought about "through various forms of stress," such as exposure to cigarette smoke.

However, they note that what is less understood is how specific epigenetic changes might alter key genes and their signaling, and how that, in turn, links to tumor formation in lung cancer.For their study, the researchers grew human bronchial cells - the type of cell that lines the airways of the lungs - in the laboratory and bathed them with a liquid form of cigarette smoke every day for 15 months. They note that bathing the cells in this way for this length of time is the equivalent to smoking one to two packs of cigarettes per day for 20 to 30 years. The team found that after 10 days, the smoke-exposed cells showed higher amounts of DNA damage compared with cells that had not been exposed to the simulated cigarette smoke.

The DNA damage was the sort that occurs in response to reactive oxygen species, or free radicals, which are oxygen-containing compounds that are known to be present in cigarette smoke.

In the period between 10 days and 3 months of exposure to cigarette smoke, the cells showed a two- to fourfold rise in levels of EZH2, which is a hormone that silences genes. Previous work had shown that this hormone can be a precursor to abnormal DNA methylation.

After the 3-month point, EZH2 leveled off and there was a two- to threefold rise in DNMT1, which is an enzyme that maintains DNA methylation in a variety of genes known as tumor suppressor genes, which normally stop tumor formation.

The enzyme was keeping the DNA methylation in the start location of the genes, effectively silencing the genes and thus blocking them from preventing uncontrolled cell growth.

In the period between 3 months and 6 months of cigarette smoke exposure, the levels of EZH2 and DNMT1 fell away, but their effect on DNA methylation was still present at 10 and 15 months.

The researchers found evidence of reduced expression in hundreds of genes - including BMP3, SFRP2, and GATA4, and other key tumor suppressor genes. They also found a significant increase - five times or more - in signals related to a cancer-causing gene called KRAS, mutations in which are found in smoking-related cancer.