Genes Linked to Smoking Affinity, Smoking-Induced Lung Cancer

 PHILADELPHIA—Research shows that genetic makeup may offer a clue to an individual’s affinity for smoking and propensity to develop lung cancer, investigators said at the annual meeting of the American Association for Cancer Research (AACR).

Margaret R. Spitz, MD, chair of the Department of Epidemiology, M.D. Anderson Cancer Center, and her colleagues evaluated a variety of genetic differences that may influence smoking behavior. They found that individuals with particular subtypes of a receptor gene for the neurotransmitter dopamine are more susceptible to becoming addicted to nicotine than individuals without these dopamine receptors.

“Individuals with the differences in these genes involved in the brain’s reward system started smoking at younger ages and were less likely to attempt quitting,” she said. Based on these findings, it may be possible to identify individuals who are genetically predisposed to become dependent on tobacco and attempt more targeted interventions to achieve smoking cessation.

The researchers also investigated the incidence of lung cancer in smokers in an attempt to determine a link to inherent genetic differences between those who develop cancer and those who do not. Differences in the way the body absorbs and metabolizes carcinogens in tobacco and in the body’s ability to handle damage caused by smoke could make some smokers and former smokers more susceptible to lung cancer.

They found that risk for lung cancer was a product of both environmental exposure to smoking and genetic susceptibility. “Individuals with susceptible genotypes or phenotypes tend to develop lung cancer at earlier ages and with lower levels of tobacco exposure than do individuals with nonsus-ceptible genotypes,” Dr. Spitz said.

On the other hand, she noted, the genetic component in risk tends to be lower at high dose levels of tobacco carcinogens, when the environmental influence may overpower genetic predisposition.

Using a blood test as one indicator of increased susceptibility, Dr. Spitz’s group was able to stratify some individuals into a sensitive subgroup. This test involved taking white blood cells from the patients’ blood, growing them in culture, exposing them to chemicals that cause genetic change, and counting the genetic damage. The frequency of the genetic changes was then quantified to assess mutagen sensitivity.

Higher Risk in ‘Sensitive’ Subgroup

The investigators found that individuals termed sensitive were four to five times more likely than others to develop lung cancer. Moreover, if these sensitive individuals were heavy smokers, they were 28 times more likely than nonsmoking controls to develop lung cancer.

“The ability to identify smokers with the highest risk of lung cancer has substantial implications,” Dr. Spitz said. “These subgroups could be targeted for intensive lung cancer screening and smoking cessation interventions and could be enrolled in cancer prevention trials.”

In the near future, she said, with genetic testing becoming more readily available, it may be possible to test for 50 to 100 genes at a time to analyze an individual’s genetic signature. Such testing will involve microarray technology capable of performing large-scale and low-cost genotyping using automated workstations that can extract DNA from blood samples and perform DNA amplification, hybridization, and detection.

“The initial chip being developed will include putative genes for lung cancer susceptibility as well as nicotine addiction,” Dr. Spitz said, adding that this will lead to challenging ethical, social, and informatics considerations.

Cancer Types in Nonsmokers

Another study presented at the meeting found that nonsmokers suffer from a different spectrum of lung cancer types than smokers. Co-researchers of the study were Kirsi H. Vahakangas, MD, PhD, assistant professor, Department of Pharmacology and Toxicology, University of Oulu, Finland, and Curtis C. Harris, MD, chief, Laboratory of Human Carcinogenesis at the National Cancer Institute.

The investigators analyzed p53 mutations in lung cancers from 132 nonsmoking women, 121 of whom had never smoked. The researchers found more adenocarcinomas in this cohort of women than are typically seen in smokers with lung cancer.

When the researchers analyzed the genetic changes in the p53 tumor-suppressor gene in these nonsmoking women, they found the changes were significantly different from those previously identified in smoking-associated lung cancers. Furthermore, even after 15 years of smoking cessation, the ex-smokers in the study were found to have p53 genetic changes that were similar to those previously observed in tumors of current smokers.

“As our understanding of the genetic changes that underlie lung cancer expands, we will be able to better identify the causes of the cancer. This is because different causative agents–for example, tobacco smoke and radon–tend to produce different genetic changes in cancer-related genes,” Dr. Harris said.

He concluded that “the mutation spectrum among the never-smokers differed clearly from the one found in smoking-associated lung cancers. However, even after 15 years of smoking cessation, ex-smokers have a p53 mutation frequency characteristic of current smokers.”