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the damage to DNA and maintain genomic inte grity, cells have developed specific
damage repair pathways (Mann uss et al. 2011). There are five main pathways each
dealing with a specific damage, including nucleotide excision repair, mismatch
repair, base excision repair, homologous recombination, and nonhomologous end
joining pathways (Ataian and Krebs 2006) (Fig. 10.3).
Depending on the intensity and severity of damage, cells utilize specific repair
pathways like in case of tobacco smoke induced DNA adducts (PAH-DNA) cells use
nucleotide excision repair pathway which consists of a series of proteins (Rouillon
and White 2011) and the commonly studied in cancers are excision repair cross
complementing (ERCC), XPA, XPC, ERCC1, ERCC2/XPD, ERCC4/XPF, and
ERCC5/XPG (Kiyohara et al. 2010; Kiyohara and Yoshimasu 2007). Similarly in
order to repair large double strand breaks cells utilize homologous recombination
and nonhomologous end joining pathways which also consists of several proteins
like RAD51, ataxia telangiectasia-mutated, and x-ray repair cross complementing
(XRCC) proteins (Mladenov and Iliakis 2011). Base excision repair pathway is
involved to repair the apurinic/apyrimidinic sites like 7,8-dihydro-8-oxoguanine
(8-oxo-G), created by reactive oxygen/nitrogen species (Kryston et al. 2011).
Besides, some alkylating agents cause addition of alkyl groups to nucleotide
bases, for example, O6-methylguanine (O6-meG) formation. Such damages are
Fig. 10.3 DNA repair pathways in mammals. Adapted from Harper’s Illustrated Biochemistry
30th Edition
10 Genetic Polymorphism and Their Role in Lung Cancer 327
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repaired by O6-meG-DNA methyltransferase protein (MGMT) (Christmann et al.
2011).
It has been found that individuals with a lower DNA repair capacity are prone to
develop diseases including lung cancer (Shen et al. 2003). Since there are several
proteins involved in each of the repair pathways and many of them are polymorphic
in nature various epidemiological studies have been conducted to see the effect of
specific SNPs in genes involved in repair pathways and their effect on the risk of
developing cancers. A meta-analysis by Vineis et al. (2009), has concluded that
several polymorphisms in APEX/APE Ile64Val (base excision repair), XRCC1
Arg194Trp and Arg399Gln (double strand repair), ERCC1 Asn118Asn, ERCC2
Lys751Gln, ERCC5 His64His and His1104Asp, XPA G23A 4 (nucelotide exci-
sion repair), MGMT Leu84Phe (alkylation damage), and OGG1 Ser326Cys (base
excision repair) could affect the risk of lung cancer. Another study has shown that
polymorphisms in ERCC1, ERCC2 could affect the survival and response of drugs
used in NSCLC (Olaussen et al. 2006). Polymorphism in XRCC4 has also been
studied and found to incre ase the risk of lung cancer (Yu et al. 2011). OGG1 which is
involved in BER and repairs 8-oxo-G which otherwise could lead to G to T
mutations has been studied by various groups and found that a SNP at Ser326Cys
increases the risk of lung cancer as the Cys allele has lower repair ability than the Ser
allele and this increased risk is more in case of smokers.
In case of enzymes involved in double strand break repair pathway a SNP in
XRCC2 at 188 position has been found to increase the lung cancer risk almost three
times more in heterozygous condition Arg188His than in individuals with
Arg188Arg genotype. ATR (ataxia telangiectasia and Rad3-related) another protein
involved in activating damage sensing proteins like P53 by phosphorylating them
plays an important role damage repair. A study has confirmed that a SNP in
ATRThr211Met could decrease the risk of lung cancer (Zienolddiny et al. 2006).
Several SNPs of MGMT gene have been studied in association with lung cancer
like Lys178Arg, Ile142Val, and Leu 84Phe. In case of Lys178Arg and Ile142Val it
has been found to increase the risk of lung cancer especially adenocarcinoma type, as
higher levels of PAH-adducts have been detected in these variants. Similarly Qiu
et al. (2014) conducted a meta-analysis and concluded that Leu84Phe SNP shows
increased risk of lung cancer in Caucasians but not in Asians.
10.4.1.3 TP53 Pathway
P53 acts an emmergency brake to maintain the genomic integrity by sensing the
DNA damage and inducing cell cycle arrest to allow DNA damage repair and
apoptosis in cells were damage cannot be repaired (Levine and Oren 2009). P53 is
regulated by MDM2, also called HDM2 which is itself induced by P53, by ubiquitin
mediated degradation (Bond et al. 2005, 2006). Several SNPs have been identified in
TP53 but most of them have no role in cancer particularly those in introns and
synonymous in nature. Although a SNP in intron3 a 16 bp insertion has been found
to increase the risk of some cancers (Costa et al. 2008; Boldrini et al. 2008) and also
a synonymous SNP at 36 codon has been shown to reduce the TP53 mRNA levels
and decreasing its ability to induce apoptosis (Candeias et al. 2008). Only two SNPs
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(Pro47Ser and Arg72Pro) have been studied in TP53 which have a demonstrated
role in modifying the risk of cancers including lung cancer.
Pro47Ser
Located at codon 47 of transactivation domain this SNP has been studied by various
groups to find its association with the risk of cancer. But it has only been reported in
African origins at the rate of 5% and not so far in any other population (Felley-Bosco
et al. 1993). This SNP is important with respect to apoptotic ability of P53 as Ser46
which is phosphorylated by p38 and homeodomain-interacting protein kinase
2 (HIPK2) enhances the transcription of apoptosis related genes and so affects the
P53 mediated apoptosis, requires a Pro residue adjacent to it (Kruse and Gu 2008).
So replacement of Pro by Ser at codon 47 will affect the ability of P53 to induce
apoptosis and so increased risk of cancer (Kurihara et al. 2007).
Arg72Pro
The SNP at codon72 is the most commonly studied among different SNPs in TP53
gene. It has been found from the comparative analysis in primates that Pro 72 variant
is the ancestral one but the Arg72 variant happens to be at a higher freque ncy in some
populations (Puente et al. 2006), besides, it has also been noted that the Pro 72 variant
is found at higher frequency in populations living near to equator and have suggested
that it might play a role in protection from UV induced effects or some environmen-
tal factors (Beckman et al. 1994; Sjalander et al. 1996). Although it is the most well
studied polymorphism but the results have been inconsistent especially from indi-
vidual case control studies. Earlier meta-analysis as the one by Van Heemst et al.
(2005), suggested a weak cancer risk in those with homozygous Pro72 variant. A
recent meta-analysis by Chao et al. (2013) also suggested that TP53 codon72 may
weakly modify the risk of lung cancer in particular for adenocarcinoma in
non-smokers. Another meta-analysis has concluded that Pro 72 variant is predomi-
nantly found in Asian lung cancer patients, so it might suggest that it is the risk factor
for lung cancer in Asians, although no statistically significant difference was
observed (Wang et al. 2013).
In case of MDM2, a negative regulator of P53, various polymorphisms have been
studied but only SNP that has got attention is the T30 9G in the first intron of the
MDM2 gene. Interestingly the G allele has been found to lead to higher transcription
of MDM2 in females possibly because of female hormones (Bond et al. 2004, 2006).
Various epidemiological studies have tried to found the link between SNP309 and
lung cancer but majority has not seen any association between them (Hu et al. 2006;
Pine et al. 2006). Although a meta-analysis by Wo et al. ( 2011) concluded that G
allele carriers have increased lung cancer compared to T allele carriers.
10.4.1.4 Inflammatory Pathways
Tobacco smoking exposure has been one of the several factors responsible for
inducing inflammatory response in lungs (Balkwill and Coussens 2004). There
have been several evidences that chronic inflammation increases the risk of lung
cancer, as inflammation leads to recruitment of immune cells which secrete
10 Genetic Polymorphism and Their Role in Lung Cancer 329
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cytokines and also invite other cells so disturbing the tissue homeostasis (Brenner
et al. 2011) (Fig. 10.4). Smoking causes irritation of lung and the cells respond by
producing proinflammatory cytokines like interleukin 1-beta (IL-1β), IL-6, IL-8,
tumor necrosis factor alpha (TNF-α), and cyclo-oxygenase-2 (COX-2). It is now
clear that cancer cells not only produce cytokines but also over express their
receptors to avoid immune response. There has been growing evidence of cytokines
being involved in cell growth, differentiation, angiogenesis, and inhibition of apo-
ptosis in tumor cells (Pollard 2004). Since cytokines have diverse roles, various
studies have been conducted to study the effect of their polymorphic variants in
cancers. SNPs in the genes of inflammatory pathways have been associated with
change in their expression levels and so could contribute to the pathogenesis of
cancers. Various epidemiological studies have shown that SNPs in interleukin genes
may predispose individuals to lung cancer. Some of commonly studied interleukins
in lung cancers are discussed in the following paragraphs:
10.4.1.5 IL-1b and IL1RN
IL-1 is an important proinflammatory cytokine existing in two forms IL-1α and
IL-1β. While alpha form can be located in both nuclear as well as cytosolic
compartments, beta form is found in cytosolic compartment (Rider et al. 2011).
Out of these forms of IL-1, beta form is more potent in nature with respect to its
proinflammatory role and has also been found to have a role in growth and invasion
of almost all tumor cells (Wu and Zhou 2009).
Various studies have been performed to see the role of SNPs in the IL-1 βgene
such as T-31C, C-511 T, T-3893G, and C-1464G in relation to lung cancer and most
of them have a strong correlation between these SNPs and expression with NSCLC
(Zienolddiny et al. 2004; Landvik et al. 2009). Also haplotype analyses of these
SNPs showed that G3893A, G1464C, C511T, and T31C SNPs formed a specific
haplotype in NSCLC cases and were found to be associated with higher expression
of IL-1 β in the lung (Landvik et al. 2009). Besides studies also confirmed that C
Fig. 10.4 Interactions between tumor cells and infiltrating immune cells in the tumor microenvi-
ronment. Adapted from Tumor-related interleukins: old validated targets for new anti-cancer drug
development by SarraSetrerrahmane and Hanmei Xu
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allele of the SNP -C511T disrupted the TATA-box and so affected its transcription
with higher transcriptional activity (Lind et al. 2007). Some studies have studied the
effect of 86 bp VNTR polymorphism of the IL1RN (interleukin 1- β receptor
antagonist) gene and have found increased risk of lung cancer with 2 alleles of
IL1RN compared to those with 1 allele particularly in those having some kind of
inflammatory condition like atopy, asthma, etc., with no history of smoking (Wei
et al. 2011).
10.4.1.6 IL 4
IL-4 is one of the most important cytokine involved in proliferation and surviva l of
lymphocytes and is synthesized by various immune cells including activated T cells.
There ha ve been various studies which found that IL-4 is over expressed by many
tumors along with its receptor including lung cancer, besides promoting survival and
proliferation of tumor cells (Sarra and Hanmei 2017).
Various polymorphisms of IL-4 have been studied, the most common ones are
T-1099G, C-589 T, and C-33 T in the promoter region of IL-4. The results with
respect to their association have not been consistent possibly because of difference in
ethnicity and the sample size. However, studies have shown that T allele of both
C-589 T and C-33 T SNPs lead to increased IL-4 transcription by increasing the
binding of transcription factors to its promoter region and might have protective role
against cancers (Rosenwasser et al. 1995; Nakashima et al. 2002). Also a study by
Scarel-Caminaga et al. (2002), has also found that C allele of C-589 T SNP is
associated with decreased expression of IL-4.
10.4.1.7 IL-6
IL-6 is another important cytokine involved in maturation of plasma cells and
proliferation and differentiation of cytotoxic T cells (Kishimoto 1989). Besides
studies have also observed higher levels of IL-6 in cancers including lung cancer
and have been associated with poor survival. Because of its role in the pathogenesis
of cancers several targeted therapies have been used like tocilizumab, an anti-IL-6
receptor antibody which suppressed progression of tumor and angiogenesis (Hara
et al. 2016).
In IL-6 two SNPs G-174C and G-634C have been studied by various groups in
association with lung cancer. G-174C has been found to be strongly associated with
the risk of lung cancer particularly squamous cell carcinoma type and also has been
found to be associated with higher levels of this interleukin (Van den Borst et al.
2011; He et al. 2009). As far as IL-6 G-634C SNP is concerned number of studies
have seen that the G allele variant at this position increased the risk of lung cancer,
more so in patients with asthma, atopy, or other inflammatory problem and having
no history of smoking (Lim et al. 2011). The findings have also been confirmed by
Bai et al. (2013).
10.4.1.8 IL-8
IL-8 is a major inflammatory response mediator cytokine released early in response
to some injury by cells like macrophages (Hedges et al. 2000). IL-8 has been found
10 Genetic Polymorphism and Their Role in Lung Cancer 331
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to be involved in cell proliferation, tissue remodeling, and angiogenesis (Waugh and
Wilson 2008). Various studies have been conducted to understand the role of
polymorphisms in IL-8 in cancers, but so far only one SNP T-251A has been
found to have some kind of association. As Gao et al. (2010) conducted a
meta-analysis on T-251A SNP of IL-8 and concluded that this polymorphism is a
susceptibility marker for lung cancer. Since this SNP affects the expression of this
interleukin another study has shown that it decreases the risk of lung cancer
especially in females (Zienolddiny and Skaug 2012).
10.4.1.9 IL-10
IL-10 is an anti-inflammatory cytokine synthesized by macrophages and T cells
(Howard et al. 1992). Several studies have been conducted on IL-10 polymorphisms
to see if they have any effect on the risk of lung cancer. SNPs studied included
A592C, T -819C, and A-1082G but the results have been inconsistent because of
sample size, ethnic difference, etc. A study on south Indian population has
concluded that –1082G/G variant was significantly associated with the risk of
NSCLC especially in smokers (Vidyullatha et al. 2016). However, recently a
meta-analysis carried out by Jamal et al. (2019) concluded that SNP A592C might
be the risk factor for lung cancer but not T -819C and A-1082G SNPs.
10.4.1.10 TNF-Alpha
TNF-α has a complex role in cancer progression with its high and low levels having
opposite roles. Several studies have been conducted to study the role of its
polymorphisms particularly G-238A, G-308A, and G488A in different cancers. In
one study SNPs G-308 A and G488 A have been found to be associated with the
susceptibility of lung cancer (Mekinian et al. 2011). In another study by Shih et al.
(2016), it was found that G238A, G-308A had a strong association with lung cancer
susceptibility, as the AA/GA genotype at 308 SNP showed increased lung cancer
and A allele was found to have a tumor promotive effect, while AA/GA genotype at
238 SNP showed decreased lung cancer risk and it was found that A allele at this
SNP had a protective role. A study on Indian populatio n also studied TNF-α 308
SNP in lung cancer patients but did not find any association (Vidyullatha et al.
2016).
10.4.1.11 IFN Gama
IFN-γ is secreted by various immune response cells activated by antigen stimulation.
It has been reported to inhibit tumor angiogenesis (Hanahan and Folkman 1996) and
also have been found to exert anti-proliferative and anti-metabolic effects on tumors
(Chen et al. 2000). Various groups have studied the polymorphisms in IFN- γ and
their association with the risk of cancers. Some studies have shown the association
between IFN-γ 874 T/A polymorphism and cancer and suggested that T allele might
be a protective genotype in cancer as T allele produces a high level of IFN-γ by
preferential binding of nuclear factor kappa-B (NF-kB) to T alle le increasing its
transcription (Rossouw et al. 2003). Yet a recent meta-analysis showed no associa-
tion between IFN-γ 874 T/A polymorphism and cancer susceptibility (Ge et al.
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2014). Another meta-analysis on leukemia patients confirmed that no significant
association between IFN-γ 874A/T polymorphism and leukemia risk (Wu et al.
2016). A study on Indian population also showed that IFN- γ 874 A/T polymorphism
was found to be significantly associated with NSCLC risk especially in smokers
(Vidyullatha et al. 2016).
A polymorphism in IFN-γ receptor switch at position-56 (T to C) in the IFN- γ R1
promoter leads to a lower expression of the receptor and so reduced IFN-γ-mediated
immunity against intracellular microbes by at least partially blocking the pathways
which activate macrophages or process antigens (Cooke et al. 2006). Addressing the
importance of polymorphisms of IFN- γ R1 at position-56 with suscep tibility to
mycobacterial infection, a meta-analysis showed that IFN- γ R1 T-56C polymor-
phism is possibly associated with increased TB risk in Africans, but not in Asian or
Caucasians. Another study also showed that the 56 CC genotypes of IFN-g receptor-
1 were significantly associated with NTM infection (Poopak et al. 2017).
10.4.1.12 COX-2
Cyclooxygenase-2 (COX-2) convert s arachidonic acid to prostaglandins. Contrary
to COX-1, which is ubiquitous and regulates normal physiologic function, COX-2 is
induced by inflammatory stimuli, growth factors, mitogenic substances, and
oncogenes (Williams et al. 1999). In addition to its role in the inflammatory
response, it may play an important role in carcinogenesis. Potential mechanisms of
carcinogenesis include dysregulation of cell growth, inhibit ion of apoptosis, inter-
ference with immune surveillance, and angiogenesis stimulation (Gridelli et al.
2002). It has been observed that certain cancers overexpress the COX2 (Wolff
et al. 1998), and also the activity of COX2 has been found to be affected by certain
polymorphisms (Tan et al. 2007). Several SNPs have been studied in COX2, one of
them is A 1195G, which has been found to influence the expression of COX-2,
while the A allele showed higher transcription rate than G allele (Zhang et al. 2005).
Another SNP, G 765C, has been reported to lead to a lower expression of COX-2
when C allele is present at this SNP (Kristinsson et al. 2009). Another SNP at 3 UTR
(8473) has been studied in association with lung cancer and found to show increased
risk of NSCLC (Campa et al. 2004).
10.4.1.13 TLR4
Toll-like receptors (TLRs) are known to act sensors of innate response to invaders
which lead to activation of various transcription factors like NF-κB to induce
expression of inflammatory genes to counter the invading organisms. Till date
there have more than 10 types of TLRs identified each with a specific role
(Abdelhabib et al. 2018). Although various polymorphisms have been studied in
TLRs in association with susceptibility to cancers (Misch and Hawn 2008) but only
TLR4 polymorphism has been found to show some association with lung cancer. In
one study by Kurt et al. (2016) two SNPs at 896 and 1196 nucleotide position
(rs4986790 and rs4986791), respectively, were studied and found that a higher risk
of lung cancer with CT allele was present at 1196 position compared to CC allele but
did not find any association with SNP at 896 position. Another study investigated the
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role of TLR4 rs4986790 SNP in response to chemotherapy in non-small cell lung
cancer and concluded that loss of function of TLR4 alleles did not affect the overall
survival in non-small cell lung cancer (NSCLC) patients (Vacchelli et al. 2012).
10.5 Conclusion
In conclusion, a number of SNPs in the pathways described above have been found
to be associated with the risk of lung cancer, but none of these SNPs has yet been
brought to clinical use. To put a SNP into clinical practice, the statistical association
must be strong enough and must show uniformity among different populations,
which is lacking in lung cancer. Researchers have shif ted the association studies
from single SNPs to genome wide association studies but the results so far have not
been encouraging. Keeping in view the limited success of SNPs or haplotype to act
as biomarker, it can be argued that there is a need to focus more on driver mutations
in different cancers. It can be speculated that SNPs being common genetic variation
have no speci fic role in predisposing the individuals to a particular type of cancer.
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