DNA Damage and Lung Cancer Risk in Tobacco Smokers- Juniper Publishers
Juniper Publishers-Journal of Cell Science
Abstract
Purpose: Lung cancer is currently the leading cause
of cancer death in the world. Although the rates of lung cancer
mortality have started to decrease in most industrialized countries, the
long time lag between the peak of cigarette consumption and lung cancer
development will assure a long life for the epidemic. We reviewed the
four epidemiological studies that have examined the dose-response
relationship of polycyclic aromatic hydrocarbons (PAH)-related DNA
adducts with lung cancer using 32P-postlabeling by pooled- or
meta-analytic approach. Our purpose was to evaluate if the presence of
high levels of PAH-related adducts in peripheral blood are associated
with increased risk of lung cancer in tobacco smokers.
Results: Meta-analyses of case-control and cohort
studies with a final data set containing data for 1,028 lung, oral and
bladder cancer patients and 1,084 controls showed higher frequency of
DNA damage in smokers in respect to referents. When only lung cancer was
considered, smokers were having 79% (95% Confidence Interval 0.33-1.25)
higher levels of PAH-related adducts as compared to controls. Pooled
and metaanalysis of longitudinal prospective studies, were the
measurement of adducts was performed in peripheral blood that was
collected years before cancer onset, confirmed that the production of
PAH-related DNA adducts was associated with lung cancer in smokers with
an overall estimate of 34% increase as compared to referents (95%
Confidence Interval 1.10-1.64).
Conclusion: Pooled and meta-analysis indicate that
smokers with greater levels of DNA damage have increased risk of lung
cancer. In prospective longitudinal studies, the overall excess of
adducts in smokers with lung cancer in respect to controls supports the
value of adducts as a predictive biomarker, that might be used to select
high risk subjects for cancer screening programs.
Keywords: DNA adducts; Lung cancer; Risk Introduction
Lung cancer is currently the leading cause of cancer
death in the world [1]. In the past century, lung cancer was extremely
rare and represented 2,3] , whereas becomes the leading cause of cancer
death in out rime [1]. During the last decades, the role of tobacco
smoking in lung cancer etiology has accumulated [4,5]. Although the
rates of lung cancer mortality have started to decrease in Western
countries [1], smoking attributable deaths are even projected to
increase due to the surge in tobacco consumption among young people [6].
The low-dose computed tomography screening, along with smoking
cessation programmes, appears to be one of the potentially most useful
strategies able to improve the current poor survival associated with
lung cancer [7]. Nevertheless, additional efforts for early detection of
lung cancer, in particular, molecular biomarkers are still necessary,
which may improve the selection of individuals for screening programs
[8].
Tobacco smoke contains more than 3,500 chemicals [4],
of which 73 tumor-initiating carcinogens either in humans and animal
models, including some polycyclic aromatic hydrocarbons (PAHs) [4],
compounds capable to bind DNA covalently, inducing PAH-related DNA
adducts [9-11]. DNA adducts, if unrepaired, may lead to mutations in
tumor suppressors and oncogenes [12]. PAH-related DNA adducts represent
an integrated biomarker of environmental exposure to carcinogenetic
compounds [13-15], and reflect the capability of each individual to
metabolically activate carcinogens and repair DNA damage [16-19]. The
levels of adducts in lung tissues have been shown to correlate with
tobacco smoke intensity in a few investigations [11,15,20,22].
Nevertheless, there were the exception of the studies of Van Schooten et
al. [23], and Chen et al. [24], Wiencke et al. [25], and Peluso et al.
[26] demonstrated that peripheral blood is a valid surrogate to estimate
adduct burden in respiratory tissue. An association of PAH-related
adducts with aberrant DNA methylation has been even shown [27]. The
occurrence of genotoxic events with the induction of various cancers,
including lung cancer, has prompt interest in DNA adduct dosimetry
studies in humans for studying the predictivity of PAH-related DNA
adducts for human cancer [12]. The central question is whether DNA
damage, in the lung tissue, truly causes cancer. If so, it might be
employed such as molecular biomarkers of lung cancer risk. Conversely,
whether the base alterations are caused by tumor progression, and
thereby they are just a bystander, so their frequency would not predict
cancer risk.
In the current study, we have reviewed the
epidemiological studies that have examined the dose-response
relationship of PAH-related DNA adducts with cancer using
32P-postlabeling [28-30] by pooled- or meta-analytic approach [31-33].
Most of the dosimetry studies were conducted analyzing blood cells, the
easiest method that provides a large amount of DNA [28], which is widely
considered a reliable surrogate target of bronchial mucosa [25,26]. Our
purpose was to evaluate if the presence of high levels of PAH-related
DNA adducts in peripheral blood are associated with increased risk of
lung cancer in tobacco smokers, prompting its use in screening programs.
Results and Discussion
In the present review, we have analyzed the four
investigations that have evaluated the association between PAH- related
DNA adducts and human cancer in peripheral blood by pooled- or
meta-analytic approach [31-34].
Case-control and cohort studies
In 2003, Veglia et al. [34], performed a
meta-analysis of seven studies that investigated the association of
PAH-related DNA adducts with human cancer [33,35-41]. Lung, oral and
bladder cancer patients were included. Six investigations analysed
adducts in peripheral blood and one in lung tissue. Six were
case-controlled studies and one was a case-control study on lung cancer
nested within a cohort. The data set included 691 cancer patients and
632 healthy controls. In that meta-analysis, smoker cases had 83%
greater levels of adducts than controls (95% confidence interval (C.I.),
0.44-1.22). Conversely, findings were negative or contradictory in
ex-smokers and non-smokers. In 2008, Veglia et al. [32], added two
cohort studies [33,42] to the data set of the previous meta-analysis
[34], obtaining 1,028 cancer cases and 1,084 controls. Even in this
case, the levels of PAH-related DNA adducts were associated with the
occurrence of various cancer (lung, bladder and oral mucosa), with
smokers having on average 73% greater amounts of adducts as compared to
controls. When only lung cancer disease was evaluated, a higher
frequency of DNA damage was found in smokers that were having 79% (95%
C.I. 0.33-1.25) greater levels of PAH-related adducts as compared to
referents. Conversely, none associations or contradictory findings were
observed among ex-smokers and non-smokers.
In 2006, Bak et al. [33] examined four lung cancer
case- control study [37-40], and two cohort studies [33,36]. Where the
formation of PAH-related DNA adducts was measured in case controlled and
cohort studies. In this report, the metaanalysis was restricted to lung
cancer and smokers, with a final data set of 397 cancer cases and 374
controls. In that study, Bak et al. [33] found a difference between lung
cancer patients and controls with cases having 78% (95% C.I. 0.29-1.27)
higher levels of adducts as compared to controls.
Longitudinal prospective studies
In 2008, Veglia et al. [32] performed a pooled
analysis of three longitudinal prospective studies [33,36,42]. Where all
the biological samples were collected years before lung cancer onset.
In the data set were included:
I. One study from the Danish prospective Diet, Cancer and Health cohort study with a case-cohort design [33]
II. A nested case-control study within the European
EPIC cohort, including France, Denmark, Germany, Greece, Italy,
Netherlands, Norway, Spain, Sweden, United Kingdom [42].
III. A nested case-control study within the Physicians' Health Study [36].
The final data set consists of 446 lung cancer cases
and 1,498 controls having a follow-up period of 51-137 months. In this
study, the levels of PAH-related DNA adduct were higher in smokers who
developed lung cancer. An Odds Ratio of 8.38 (95% C.I. 6.15-11.41) was
indeed found in lung cancer smoker patients as compared to non-smokers.
An increase of 14% per unit standard deviation supported the predictive
value of adducts for lung cancer. In 2014, Gilberson et al. [31],
performed a meta-analysis on DNA adducts and lung cancer from four
longitudinal prospective studies. In this meta-analysis, the nested
case-controlled investigation conducted within the Spanish EPIC study
[31] was added to the data set, which was previously considered in the
pooled analysis of Veglia et al. [32]. The final data set was of 2,341
subjects with a follow-up range of 51-137 months. In this study, the
generation of adducts was associated with lung cancer in smokers with an
overall estimate of 34% increase as compared to controls (95% C.I.
1.10-1.64). No associations or contradictory findings were detected in
exsmokers and non-smokers.
Taken together, there is an agreement with the
proposition that increased levels of PAH-related DNA adducts are
associated with lung cancer for individuals with high exposure to
tobacco smoke carcinogens. Nevertheless, this depends on whether the
adducts cause lung cancer or the generation of DNA damage is influenced
by early effects of cancer itself. The interpretation of the
meta-analyses are indeed limited by the fact that in case-control
studies the levels of biomarker may reflect the cancer disease rather
than the etiology. However, two exceptions are represented by the
studies of Veglia et al. [32] and Gilberson et al. [31]. The importance
of these reports rests on the measurement of PAH-related adducts in
peripheral blood that was collected years before cancer onset, thus
ruling out the possibility that the greater amounts of adducts were due
to metabolic changes associated with an already existing lung
cancer.Thus, prospective longitudinal studies suggest that increased
levels of PAH-related DNA damage in smoker that will develop lung cancer
can be considered a cancer risk factor, because if unrepaired, adducts
may lead to mutations and ultimately trigger carcinogenesis.
Conclusion
Pooled and meta-analysis indicate that smokers with
greater levels of DNA damage have increased risk of lung cancer. These
findings corroborate the epidemiologic data supporting the association
of lung cancer with smoking habit. In prospective longitudinal studies,
the overall excess of adducts in smokers with lung cancer in respect to
controls supports the value of adducts as a predictive biomarker, that
might be used to select high risk subjects for cancer screening
programs. We may argue that phenotypes characterized by high levels of
PAH-related adducts may arise in susceptible individuals at high risk of
lung cancer as consequence of disorders in regulatory circuitry that
act to maintain cell homeostasis and DNA integrity after carcinogen
exposure to tobacco smoke constituents [17]. However, it should be also
relevant to consider for screening programs other biomarkers such as
measurements of epigenetic alterations [43,44] as well as DNA damage at
sequence level [45].
Acknowledgement
This study was partially supported by the
"Associazione Italiana per la Ricerca sul Cancro", Milan, Italy, and the
"Istituto Toscano Tumori", Florence, Italy.
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