PHILADELPHIAResearch shows that genetic makeup may offer
a clue to an individuals 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
brains 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 bodys ability to handle damage caused by
smoke could make some smokers and former smokers more susceptible to
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.
Spitzs 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
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
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
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 individuals 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 agentsfor example,
tobacco smoke and radontend 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