|Smoking’s Effects on Genes May Play a Role in
Lung Cancer Development and Survival
Smoking plays a role in lung cancer development, and now scientists
have shown that smoking also affects the way genes are expressed,
leading to alterations in cell division and regulation of immune
response. Notably, some of the changes in gene expression persisted
in people who had quit smoking many years earlier. These findings
by researchers at the National Cancer Institute (NCI), part of
the National Institutes of Health, appeared in the Feb. 20, 2008,
issue of PLoS ONE.
"Smoking, we are well aware, is the leading cause of lung
cancer worldwide," said NCI Director John E. Niederhuber,
M.D. "Yet, a mechanistic understanding of the effects of smoking
on the cells of the lung remains incomplete. This study demonstrates
an important piece of this complicated puzzle. Greater understanding
of the genetic alterations that occur with smoking should provide
greater insight into the development of cellular targets for treating,
and possibly preventing, lung cancer."
"We were able to look at actual lung tissue, tumor and non-tumor,
taking into account the differences by gender, verifying the smoking
status by measuring levels of cotinine, a metabolite of nicotine,
in participants' plasma, and confirming results in independent
samples," said Maria Teresa Landi, M.D., Ph.D., in NCI's Division
of Cancer Epidemiology and Genetics, the first author of the study
To investigate the effects of smoking on gene activity in lung
tissue, the researchers examined the gene expression profiles —
patterns of gene activity — in early-stage lung tumors and
non-tumor lung tissue of smokers, former smokers, and people who
had never smoked cigarettes. Gene expression was measured in 58
fresh-frozen tumor and 49 fresh-frozen non-tumor samples from 74
participants of the Environment And Genetics in Lung cancer Etiology
(EAGLE) study, a large lung cancer study that was conducted in
the Lombardy region of Italy. Adenocarcinoma tumor samples were
evaluated in this study because adenocarcinoma is the most common
type of lung cancer, and it occurs in both smokers and people with
no history of smoking. The participants were 44 to 79 years of
age, and 28 were current smokers, 26 were former smokers, and 20
had never smoked. The researchers also obtained detailed medical
information about the participants (for example, whether individuals
had previous lung diseases or chemotherapy) and biochemically confirmed
participants' smoking status.
Using microarray techniques, which allow researchers to look at
the activity of thousands of genes simultaneously, they identified
135 genes that were differently expressed in tumors of smokers
vs. people who had never smoked. Among these genes, 81 showed decreased
expression and 54 showed increased expression in tumor tissue.
Most of the genes showing significantly increased expression,
e.g., TTK, NEK2, and PRC1, are involved in cell cycle regulation
and mitosis. The cell cycle is a step-wise sequence of events in
which a cell grows and ultimately divides to produce two progeny,
or daughter, cells. During the cell cycle, the chromosomes of the
parent cell are duplicated and then, in a step called mitosis,
divided equally between the daughter cells, ensuring that each
daughter cell inherits a complete set of chromosomes. The cell
apparatus responsible for the proper division of chromosomes is
called the mitotic spindle.
"Our results indicate that smoking causes changes in genes
that control mitotic spindle formation," said Jin Jen, Ph.D.,
in NCI's Center for Cancer Research, a senior author of the study
report. "Irregular division of chromosomes and chromosome
instability are two common abnormalities that occur in cancer cells
when the chromosomes do not separate equally between the daughter
cells. Therefore, changes in the mitotic process are very relevant
in the development of cancer." Several of the identified genes
have been suggested in the past as potential targets for cancer
The researchers also found similar expression of many genes among
current smokers and former smokers in tumor tissue. Several of
these genes, such as STOM, SSX2IP, and APLP2, remained altered
in participants who had quit smoking more than 20 years before
the study. Therefore, smoking seems to cause long-lasting changes
in gene expression, which can contribute to lung cancer development
long after cessation.
Looking at non-tumor lung tissues, the team found decreased activity
for 73 genes and increased activity for 25 genes in current smokers.
The genes most affected by smoking play a role in immune response-related
processes, possibly as a lung defense mechanism against the acute
toxic effects of smoking. However, non-tumor tissues seem to be
able to recover from the effects of smoking. The researchers did
not identify significant changes in the immune response-related
genes in former smokers.
To gain a better understanding of the impact of smoking-related
changes in gene expression on lung cancer survival, the researchers
compared the overall gene expression smoking profile in lung tumor
and non-tumor tissues with survival. They found that the altered
expression of the cell cycle-related genes NEK2 and TTK in non-tumor
tissues was associated with a three-fold increased risk of lung
cancer mortality in smokers.
"Our data provide clues on how cigarette smoking affects
the development of lung cancer, indicating that the very same mitotic
genes known to be involved in cancer development are altered by
smoking and affect survival. More studies are needed to confirm
that the gene expression changes are due to smoking and affect
tumor development or progression," said Landi. "If confirmed,
these genes could become important targets for preventing and treating lung
About 90 percent of lung cancer deaths among men and almost 80
percent of lung cancer deaths among women can be attributed to
smoking. In 2006, approximately 20.8 percent of U.S. adults were
cigarette smokers. Cigarette smoking remains the leading preventable
cause of death in the United States, causing an estimated 438,000
deaths, or about one out of every five deaths each year.
For more information on research in Dr. Landi's group, please
go to http://dceg.cancer.gov/about/staff-bios/landi-maria.
For more information on research in Dr. Jen's lab, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5542.
For more information about the EAGLE study, please go to http://dceg.cancer.gov/eagle.
For more information about cancer, please visit the NCI website
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Landi MT, Dracheva T, Rotunno M, Figueroa, JD, Liu H, Dasgupta A,
Mann FE, Fukuoka J, Hames M, Bergen AW, Murphy SE, Yang P, Pesatori
AC, Consonni D, Bertazzi PA, Wacholder S, Shih JH, Caporaso NE, and
Jen J. February 2008. Gene Expression Signature of Cigarette Smoking
and Its Role in Lung Adenocarcinoma Development and Survival. PLoS
ONE. Vol. 3, No. 2.