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9 The Role of Toll-Like Receptor (TLR) Polymorphisms in Urinary Bladder Cancer 317
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Genetic Polymorphism and Their Role
in Lung Cancer
10
Sheikh M. Shaffi
Abstract
Lung cancer is the leading cause of cancer related mortality all over the world,
partly owing to its late discovery and early progression. Despite the recent
advances made in the understanding of molecular basis of the lung cancer,
there has not been much improvement in the overall survival of patients.
Although smoking is considered to be the major risk factor for lung cancer, less
than 15% of lifetime smokers have been found to develop the disease, suggesting
there might be inter-individual differences which may contribute to risk modifi-
cation. Besides, chemical and environmental factors, genetic variations have been
implicated in the susceptibility of the disease. One of the most common types of
genetic variation is the SNPs. Many of these SNPs have been identified in major
pathways involved in development and progression of lung cancer like carcino-
gen metabolizing and detoxifying pathways, immune response/inflammatory
pathways, cell cycle regulatory pathways, etc. The SNPs not only affect the
transcription of genes and structure and function of the proteins, but also have a
potential role in diagnosis, prognosis, and even treatment selection and overall
survival of the patients. In this chapter we will discuss role of some of the
commonly studied SNPs involved in the major lung cancer pathways.
Keywords
Lung cancer · SNP · Xenobiotic · DNA repair · Inflammation
S. M. Shaffi (*)
Department of Biochemistry, Government Medical College, Anantnag, Jammu and Kashmir, India
#
The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2021
A. S. Sameer et al. (eds.), Genetic Polymorphism and Cancer Susceptibility,
https://doi.org/10.1007/978-981-33-6699-2_10
319
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Abbreviations
COMT Catechol-O-methyltransferase
COX-2 Cyclo-oxygenase-2
CYP Cytochrome P450
ERCC Excision repair cross complementing
ETS Environmental tobacco smoke
GSTs Glutathione S-transferases
IFN- γ Interferon gamm a
IL Interleukin
MDM2 Murine double minute 2
NATs N-acetyl transferases
NNKs 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
NSCLC Non-small cell lung cancer
PAHs Polycyclic aromatic hydrocarbons
SCC Squamous cell carcinoma
SCLC Small cell lung cancers
SNP Single nucleotide polymorphism
TLR Toll-like receptors
TNF-α Tumor necrosis factor alpha
10.1 Introduction
Cancer is the most feared and complex medical condition. Cancer can be defined as
an autonomous growth that is unresponsive to normal grow th factors and antigrowth
signals. Cancer cells progressively loose the differentiated characteristics and
functions of tissue of origin and revert to growth and antigenic properties which
are characteristic of fetal cells. A number of genetic and epigenetic changes have
been observ ed in cancer cells. Among these which are primary or secondary is still a
matter of investigation. Nonetheless, these changes have been explored to under-
stand the mechanism of carcinogenesis as well as in establishing their diagnostic,
prognostic, or therapeutic potential.
Moreover, Human Genome Project has revealed 99.9% genome similarity among
individuals. This finding has led to the hypothesis that the 0.1% genetic difference
may help in determining the susceptibility of individuals to particular diseases;
predicting the prognosis of disease as well as the response to the therapeutic
treatment. Since SNP is the most commonly observed genetic variation among
individuals, a lot of studies have been conducted to establish their role in the
management of diseases like cancer. In this chapter we will discuss the role of
some important SNPs that have been studied in the genes involved in the important
carcinogenic pathways of lung cancer.
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10.2 Lung Cancer and Its Types
Lung cancer is the leading cause of mortality among cancers, besides being the most
fearful human malignancy owing to its late discovery and early progression. The
term lung cancer is used for tumors arising from the respiratory epithelium (bronchi,
bronchioles, and alveoli). Almost 95% of primary lung cancers are epithelial in
origin and are categorized on the basis of histological appearance into Non-Small
Cell Lung Cancer (NSCLC) and Small Cell Lung Cancers (SCLC) (Zochbauer-
Muller et al. 2002).
SCLC which accounts for 15% of primary lung cancers is characterized histolog-
ically by small hyperchromatic cells with almost no visible cytoplasm, absent
nucleoli, and variable degrees of necrosis. SCLC may be distinguished from
NSCLC by the presence of neuroendocrine markers including CD56, neural cell
adhesion molecule (NCAM), synaptophysin, and chromogranin. Small cell
carcinomas are clinically aggressive with early metastasis and are usually centrally
located. Although they respond well to chemotherapy but at the time of diagnosis
they are often at advanced stages and so the patients have a poor prognosis (Midthun
and Jett 1996). The median survival of patients with limited-stage disease is reported
to be 15–18 months only.
NSCLC accounts for 85% of primary lung cancers. Histologic subtypes of
NSCLC as defined by WHO and IASLC include squamous cell carcinomas, adeno-
carcinoma, large cell carcinoma, adenosquamous carcinoma, sarcomatoid
carcinomas, neuroendocrine tumors, and unclassified tumors.
Squamous cell carcinomas are characterized histologically by cytokeratin and
intracellular bridges. They are usually centrally located endobronchial masses that
may present with hemoptysis, postobstructive pneumonia, or lobar collapse and
generally metastasize late in the disease course (Patz 2000).
Adenocarcinomas, the predominant histologic patterns of lung adenocarcinoma
include acinar, solid, papillary, and bronchioloalveolar. Adenocarcinoma cells
express cytokeratins 7 and 20. These tumors are often found in patients with
underlying lung disease and metastasize early (Travis et al. 1995).
Large cell carcinomas are poorly differentiated. These tumors are large periph-
eral masses associated with early metastases (Travis et al. 1995).
The overall prognosis for NSCLC is dismal with 5-year survival generally
reported below 10% (for all patients).
10.3 Risk Factors of Lung Cancer
10.3.1 Smoking
The link between smoking and lung cancer is beyond dispute. Tobacco smoke
consists of a complex mixture of over 4000 different chemical, more than 40 of
which have been described as carcinogens in animals by the International Agency
for Research on Cancer (IARC) (Fig. 10.1). Polycyclic aromatic hydrocarbons have
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been shown to induce lung cancer in animals (Woltebeek et al. 1995). Most studies
have demonstrated that the risk of lung cancer is related to exposure of tobacco
smoke that is the number of cigarettes smoked and duration of exposure (IARC
1986; USPHS 1989), with the duration of smoking being stronger factor than
number of cigarettes smoked per day (Doll and Peto 1978).
10.3.2 Second Hand Smoke/Environmental Tobacco Smoke (ETS)
ETS/second hand smoke is the exhaled smoke of the smokers and the sidestream
smoke released during smoking. The sidestream smoke is gaseous in nature
consisting of some carcinogens in higher concentration like benzo(a)pyrene, nitro-
samine and 210Po, etc. (Lam and Du 1988). Being lighter it can penetrate into the
peripheral parts of lung causing particularly adenocarcinoma, among non-smokers
(Wynder and Goodman 1983). ETS is classified as a class A carcinogen and is found
to be respon sible for around 20% of lung cancers in non-smokers (USEPA 1992).
10.3.3 Air Pollution
10.3.3.1 Indoor Pollution
The fumes arising during cooking have been described as a significant risk factor
among non-smokers for lung cancer (Metayer et al. 2002; Wang et al. 1996a, b). The
fumes from vegetable oils have been found to contai n known mutagens like benzo
(a)pyrene, benzo(a) anthracene, and dibenz (a,h) anthracene (Chiang et al. 1999).
Besides volatile substances produced under similar conditions from vegetable oils
Constituents of smoke
Concentration/cigarette
Particulate matter
15-40mg
CO
10-23mg
Nitrogen oxides
100-600μg
Benzene
20-50μg
Nitoso compounds
0-200ng
Vinyl chloride
1.3-16ng
Benzene(a) anthacene
20-70ng
4-aminobiphenyl
2.4-4.6ng
2-naphthylamine
1.7-22ng
Benzo(a)pyrene
20-40ng
Adopted from; IARC database
Fig. 10.1 Amount of some common mutagens present in cigarette
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have been found to be genotoxic (Wu et al. 1999), making the link between the
fumes from cooking oil and risk of lung cancer more clear.
The smoke produced from burning of coal which is used for cooking and
sometimes for heating purposes during winter time has been included in the list of
risk factors especially for non-smokers. A study by Mumford et al. (1987), showed a
strong correlation between indoor air benzo(a)pyrene concentration and high lung
cancer mortality rates particularly from adenocarcinoma in women. Household coal
burning has also been found to be a strong risk factor for lung cancer in other studies
(Wang et al. 1996a, b).
Various studies have been conducted to evaluate the risk if any associated with
smoke produced from incense burning and lung cancer but no such effect was
observed (Koo et al. 1996). Other indoor pollutions, such as exposure to smoke
produced from kerosene stove cooking, etc., have also been studied but no signifi-
cant effect was observed (Koo et al. 1984).
10.3.3.2 Outdoor Pollution
In order to assess the effect of air pollution on the risk of lung cancer various studies
have been conducted but none showed any significant association (Speizer et al.
1994). Although the air particularly in urban areas has been found to contain known
carcinogens, like benzo(a)pyrene, benzene, dimethyl nitrosamine, and even radon,
arsenic, asbestos, cadmium, chromium, etc. Also diesel exhaust has been included in
a list of probable carcinogen by the IARC (IARC 1989).
10.3.4 Occupational Exposure
Among different risk factors for lung cancer, occupational exposure has also been
included and found to account for about 5–20% of all lung cancers particularly in
smokers (Samet and Lerchen 1984). Asbestos exposure is one such occupational risk
factor which has been associated with increased risk in mine workers (Stayner et al.
1996). Similarly silica which has been included by the IARC as carcinogen for
humans has been studied by v arious groups to see if there is any association with
lung cancer. But there have been conflicting results, while some studies suggested a
positive correlation Nakagawa et al. (2000) and Wang et al. (1996a, b) and others did
not find its role in causing lung cancer independently (Fu et al. 1994; Chan et al.
2000). Among other occupational exposures increased risk of lung cancer has been
observed in textile workers although statistically insignificant (Udwadia et al. 2000)
and also in benzene exposed workers increase in deaths due to lung cancer has been
observed (Hayes et al. 1996).
10.3.5 Diet
Vegetables and fruits have been proved to be good for health. Various studies have
been conducted to see if there is any protective effect of taking higher intake of
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vegetable and fruits particularly beta carotene and vitamin A against lung cancer
risk, but not a single study has been able to prove it (Alpha Tocopherol Group 1994;
Omenn et al. 1996). Preserved foods form a large part of the diet in various cities
containing N-nitroso compounds or their precursors with mutagenicity. Again some
interesting results have been observed like Miso (preserved, fermented soybean
paste) soup and pickles (excluding salted fish) were found to be associated with an
increased risk, and frequent intake of soybeans and tofu (soybean curd) a decreased
risk of lung cancer, particularly SCC (Wakai et al. 1999), was found.
10.3.6 Infections
Whether tuberculosis leads to lung cancer or not has been studied by various groups
and could not reach to any conclusion, although a study had shown a significant
increase in lung cancer risk among TB patients independent of smoking (Zheng et al.
1987).
10.3.7 Gender Differences
Studies have suggested that women are more susceptible than men to smoking
induced lung cancer (Zang and Wynder 1996). Even some studies have shown
that lower mean pack-years of smoking for women diagnosed with lung cancer
compared with men (Risch et al. 1993). The reasons for gender differences in
susceptibility to lung cancer are not clear, but endogenous and exogenous estrogens
have been implicated (Taioli and Wynder 1994).
10.4 Polymorphism and Lung Cancer
One of the most common genetic variation which leads to inter-individual difference
is the single nucleotide polymorphism. A SNP is a difference in a single nucleotide
in DNA between two individuals. Since these nucleotide variations are inherited
from parents, it may give rise to homozygous or heterozygous base variations in an
individual. It has been found that SNPs occur almost every 1000 nucleotides in a
genome which roughly means 4–5 million SNPs in an individual. SNPs can be
present in any gene so it can affect its function. Although most of the SNPs have no
effect on the function of a gene but some of them have proved to be responsible for
varied response to susceptibility to certain diseases, detoxification of
xenobiotics, etc.
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10.4.1 Polymorphism in Major Biological Pathways for Lung
Carcinogenesis
Smoking is the major cause of lung cancer (Subramanian and Govindan 2007), but
still less than 10–15% of lifetime smokers develop the disease, suggesting there are
some inter-individual that may play a role in pathogenesis of lung cancer (Wu et al.
2004). One such variation is the presence of SNPs in some of the genes involved in
detoxification of tobacco smoke, repairing of DNA damage caused by smoking and
also suppression of mutations caused by tobacco smoking (Sugimura et al. 2011).
Many of them are also present in the stress response genes and the genes involved in
immune function. Although the significance of many of these polymorphisms has
been studied; however, many more remain undiscovered. Here we will discuss the
major pathways where polymorphism of genes has been found to modify the risk of
lung cancer.
10.4.1.1 Xenobiotic Pathway
Tobacco smoke carcinogens, like PAHs (Benzo(a)pyrene), NNKs, etc. are
substances that are foreign to the human body, i.e. xenobiotics. Most of these
substances are metabolized in liver in two steps phase I and phase II (Fig. 10.2).
In phase I these xenobiotics are hydroxylated and made polar, while in phase II they
are conjugated and made more water soluble in order to remove them from body.
Cytochrome P450 genes code a number of enzymes which constitute phase I system
of body (Sim and Ingel man-Sundberg 2010). CYP genes like CYP1A1 and CYP1B1
transform benzopyrene, a tobacco carcinogen into an epoxide, B(a)P-7,8 dihydro-
epoxide (Pratt et al. 2011). Both of these are induced by tobacco smoke and also
have been found to be overexpressed in lung cancer (Kim et al. 2004). A study has
Fig. 10.2 Xenobiotic metabolism pathway. Adapted from Tim Vickers, http://en.wikipedia.org/
wiki/File:Xenobiotic_metabolism.png
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shown a positive correlation between CYP1A1 expression and PAH-DNA adduct
formation in smokers (Mollerup et al. 2006). Besides, another study has detected a
strong correlation between adduct levels and higher expression of CYP3A5, another
enzyme involved in detoxification of PAHs (Piipari et al. 2000). Similarly CYP2A6
an enzyme involved in detoxification of NNKs has been reported to affect the
smoking addiction behavior (Bloom et al. 2011).
Several epidemiological studies were conducted to assess the correlation between
SNPs in CYP genes and lung cancer, as some SNPs have been found to affect the
activity of these enzymes. Chen et al. (2011) conducted a meta-analysis to under-
stand the effect of MspI and Ile462Val polymorphisms in the CYP1A1 gene in
association with lung cancer and it was concluded that both these SNPs were
associated with increased lung cancer risk, especially among East Asians. Another
study by Xun et al. (2011), who investigated the role of SNPs in CYP1B1 like
Leu432Val, Ala119Ser, Arg48Gly, and Asn453Ser found that these SNPs were
associated with lung cancer risk with higher risk in homozygous condition like
40% higher risk in 432 Val/Val, twice more risk in 119Ser/Ser carriers that
119 Ala/Ala carriers and four times higher risk was found in those with 48Gly/Gly
genotype than 48 Arg/Arg genotype carriers. Furthermore, they found that
Asn453Ser SNP was associated with increased risk in female sex.
GSTs (glutathione S-transferases) and NATs (N-acetyl transferases) belong to
phase II enzymes and their role in xenobiotic metabolism has been also studied in
relation to lung cancer risk as they are also highly polymorphic in nature as that of
CYPs (Brigelius-Flohe and Kipp 2009). Among various SNPs in GSTs, Met139Ile
(GSTT) and Ala114Val (GSTP1) SNPs have been found to be stro ngly associated
with increased lung cancer risk (Zienolddiny et al. 2006). NAT1 and NAT2 enzymes
metabolize aryl and heterocyclic enzymes by acetylation reaction. It has been found
that there exists a polymorphism in these NAT genes and result in three variants
slow, intermediate, and fast acetylators (Agundez 2008). Various studies were
conducted to understand the effect of NAT variants on the risk of lung cancer and
it was concluded that fast acetylators of NAT were associated with increased lung
cancer risk (McKay et al. 2008).
Tobacco smoke has also been found to contain reactive species of oxygen and
nitrogen which have a demonstrated role in pathogenesis of lung cancer. Several
mechanisms are present in the body to deal with these oxidants like superoxide
dismutase, myeloperoxidase, catechol-O-methyltransferase (COM T) and micro-
somal EPHX1, etc., and they also exist in polymorphic variants (Tilak et al. 2011).
There have been studies to understand the role of the variants of antioxidants in
relation to lung cancer. Several SNPs were studied and among them Val158Met in
the COMT, His139 Arg in the EPHX, and Val16 Ala in the SOD2 have been found
to be involved in modifying the risk of lung cancer (Kiyohara et al. 2006).
10.4.1.2 DNA Damage Repair Pathway
DNA is continuously subjected to various chemical, physical, and biological insults
causing damage to it, which if remain unrepaired may lead to mutations,
rearrangements, or chromosomal aberrations (Ataian and Krebs 2006). To prevent
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