A study by Memorial Sloan Kettering researchers has produced new evidence suggesting that women are more susceptible than men to developing some types of smoking-related lung cancers.
By analyzing genetic information from the tumors of more than 3,000 lung cancer patients, the scientists found that female smokers are more likely to develop a specific genetic mutation believed to lead to lung adenocarcinoma, the most common form of non-small cell lung cancer.
One Gene, Two Mutations
The researchers focused on a gene called KRAS, which is frequently mutated in lung adenocarcinomas, and found that smokers and people who never smoked (“never smokers”) had different KRAS mutations in their tumors. Smokers usually had a mutation called KRAS G12C, while never smokers typically had a mutation called KRAS G12D. Women were more likely than men to have the KRAS G12C mutation, and they developed the disease at a younger age and with a shorter history of smoking.
The findings, published in the October 22 issue of Clinical Cancer Research, support a long-debated theory that women are more vulnerable than men to the cancer-causing effects of tobacco smoke. Molecular pathologist Marc Ladanyi, who led the study, says researchers have speculated for decades that women who smoke are at greater risk for lung cancer than men, but various analyses have produced conflicting data.
“If you look at mutations in lung cancers as a whole, the difference between men and women can be hard to detect,” Dr. Ladanyi says. “But by focusing on particular molecular subgroups within adenocarcinoma — in this case, the two distinct KRAS mutations — we can tease out the smoking-associated cases and get a clearer picture of the disparity in risk.”
Genetic Profiling of Lung Cancers
The study drew upon Memorial Sloan Kettering’s extensive database of tumor and patient information. Since 2006, nearly every patient’s lung adenocarcinoma tumor has been tested for mutations in the genes KRAS and EGFR. Almost half of all lung adenocarcinomas harbor a mutation in one of these genes.
Knowing the mutation status helps physicians plan the best treatment. For example, patients whose tumors have the EGFR mutation usually respond well to treatment with the targeted therapy erlotinib (Tarceva®), but those with a KRAS mutation do not and are given different treatments.
In addition to genetic testing, Memorial Sloan Kettering’s Thoracic Oncology Service always obtains a detailed smoking history from lung adenocarcinoma patients, such as how much they smoked, for how long, and, if applicable, how many years since they quit. The comprehensive data on each smoker allowed the researchers to examine how different types of KRAS mutations correlate with variables such as smoking history, gender, and age of diagnosis.
“We were one of the first centers to perform routine testing for these mutations in all lung cancer patients, so over the years we accumulated information from numerous patients,” says molecular pathologist Snjezana Dogan, the first author on the research article. “This allowed us to look at these KRAS mutation subsets and still have sufficiently large numbers to provide real statistical power in the analysis.”
The Role of Secondhand Smoke
In addition to suggesting an increased risk for women, the tumor genotype analysis pointed toward another conclusion — that most KRAS-mutant lung adenocarcinomas in never smokers are not caused by secondhand smoke. Otherwise, tumors of never smokers would have the same KRAS mutation (KRAS G12C) as smokers, rather than KRAS G12D.
“The extent of involvement of secondhand smoke in lung cancer is another topic under dispute, and this study provides evidence that nonsmokers whose tumors contain the KRAS G12D mutation probably didn’t develop the disease because of secondhand smoke,” Dr. Ladanyi adds.