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the microsatellite) have been studied exhaustively. The CTLA-4 + A49G SNP is one
of the most important one, located at position +49 in the first exon of the CTLA-4
gene causing a substitution of threonine to alanine at position 17 of the leader peptide
which effects its cell surface expression (Ghaderi 2011; Fernández-Mestre et al.
2009). It has been reported that CTLA-4 + A49G SNP (rs231775) exerts a differen-
tial effect on the T cell response to the viral infections, in regulating interleukin (IL)-
2 production and also in predisposing individuals to various malignancies especially
cervical cancer (Ueda et al. 2003; Su et al. 2007; Gokhale et al. 2013). While as for
CTLA-4 -C318T SNP, T allele has been shown to significantly increase the expres-
sion of both CTLA-4 mRNA and its protein and has also been reported to be
associated with the risk of cervical cancer (Hu et al. 2020; Lee et al. 2014; Wang
et al. 2002).
In one of the recent meta-analyses, it was reported that there was a significant
association between CTLA-4 + A49G SNP and CC [OR ¼ 0.822, 95% CI
0.731–0.924, p ¼ 0.001] and CTLA-4 GG + GA genotype and CC in East Asians
[OR ¼ 0.708, 95% CI 0.532–0.943, p ¼ 0.018] confirming the protective effect
of this SNP (Lee et al. 2014; Wang et al. 2002). A recent meta-analysis by Hu
et al. (2020) also reported an association between CTLA-4 -C318T SNP and
CC [T vs C: OR ¼ 1.40, 95% CI ¼ 1.12–1.76] as well as its contribution to an
individual’s susceptibility to CC among Asian population [T vs C: OR ¼ 1.56, 95%
CI ¼ 1.22– 1.99].
7.3.1.4 IL-1b
Interleukin-1β (IL-1β) is one of the important interleukin member of the cytokine
family which also includes interleukin-1α (IL-1α) and interleukin 1 receptor antago-
nist (IL-1RN) (Kang et al. 2007). The genes for all those are located within the
430-kb segment on the chromosome 2 (2q13–21). IL-1β is a proinflammatory
cytokine, which is known to play important role in cell differentiation, proliferation,
and apoptosis mechanisms. It also has an essential regulatory bearing on the function
of various cells of innate and adaptive immunity—like monocytes, macrophages,
granulocytes, natural killer (NK) cells, B-cells, subsets of T-cells, etc., (Dinarello
2009, 2011 ). The gene locus encoding IL-1β is reported to be highly polymorphic
and at least 20 different genetic polymorphisms have been reported so far, out of
which major SNPs exist in the 5
0
-flanking regions of the gene. These SNPs have
been found to affect the IL-1 β expression and hence its levels in the serum/tissue of
an individual by affecting the response elements located well within the promoter
regions of the gene (Chen et al. 2006).
Among all the SNPs that are known to be present in the promoter region of IL-1β
gene, two SNPs are important and most studied among all populations in the world;
these are - IL-1β -31C/T (rs1143627) and IL-1β -511T/C (rs16944). IL-1β -31C/T
SNP involves the substitution of cytosine (C) by thymine (T) at 31 position of gene
promoter while IL-1β -511 T/C SNP results in the thymine (T) to cytosine (C) sub-
stitution at 511 position (Banday et al. 2017a, b). Both of these SNPs result in the
decrease in the expression of IL-1β and hence lowering the activity of IL-1β. Both of
these SNPs do regulate essential biological and clinical processes within the
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organism to modulate the susceptibility to various diseases including cancer (Zhang
et al. 2014a , b; He et al. 2011; El-Omar et al. 2001; Chen et al. 2006).
Meta-analysis by Lee et al. (2014) reported a significant association between the
risk of CC and IL-1β-511 T allele [OR ¼ 1.380, 95% CI 1.048–1.816], and also there
was a significant association between the IL-1β-511 CC + CT genotype with the East
Asian individuals [OR ¼ 1.622, 95% CI 1.227–2.43]. A meta-analysis by Xu et al.
(2013) did also report that IL-1β +3954C/T was associated with higher risk of cancer
[OR ¼ 1.15, 95% CI: 1.01–1.30], however, for -511C/T SNP it was observed that
CC risk was less [OR ¼ 1.74, 95% CI: 1.35–2.23].
7.3.1.5 IL-10
Interleukin-10 (IL-10) is one of the essential anti-inflammatory cytokines which has
a suppressive function in cell-mediated immune responses. It is mainly secreted by
monocytes/macrophages, keratinocytes, T helper cells 1/2(Th1 and Th2 cells), as
well as by tumor cells (Moore et al. 2001). IL-10 functions as pleiotropic cytokine
which inhibits the development of Th1-type immune responses, thereby
downregulating the expression of proinflammatory Th1 cytokines and costimulatory
molecules (Moore et al. 2001). Additionally, numerous varied functions of IL-10
include the stimulation of mast cell maturation, acceleration of prolifera tion and
differentiation of B-cells, inhibiting the production of cytokines like IL-2, IFN-γ,
and decreasing the IFN-γ production by natural killer (Nk) cells and also in
interfering with the activation of macrophages (Sun et al. 2013).
IL-10 gene is present on chromosome 1 at its long arm (1q31–1q32), spanning
about 4.8 kb, and consists of 5 exons and 4 introns which encode 178 amino acid
residue protein (Eskdale et al. 1997). The 5
0
and 3
0
flanking regions of the IL-10 gene
are reported to be highly polymorphic like IL-1β and the 5
0
flanking region that
encompasses the promoter is found to contain at least 40 SNPs (Guo et al. 2018;
Howell and Rose-Zerilli 2007). Among all, only three SNPs of the IL-10 promoter
region, i.e., 1082A > G (rs1800870), 819 T > C (rs1800871), and 592C > A
(rs1800872) have been reported to influence the transcription and expression of the
gene (Ouma et al. 2008).
Numerous molecular studies have reported on the role of IL-10 SNPs in various
cancers in world population (Martínez-Campos et al. 2019; Banday et al. 2017a, b;
Ni et al. 2013; Stanczuk et al. 2001). In one of the recent meta-analyses, IL-10
-A1082G SNP was found to be significantly associated with the risk of CC in whole
population [OR ¼ 1.60, 95% CI ¼ 1.12–2.29], as well as in Asian populations (Guo
et al. 2018). Furthermore, the same report concluded that IL-10 T819C SNP
demonstrated a significant protective effect against CC but for IL-10 –C592A SNP
no significant association was reported for CC susceptibility. In previous meta-
analysis, Zhang et al. (2014a, b) had reported no association between the IL-10
-A1082G SNP and CC susceptibility. Also, Zhang et al. (2014a, b) had also
classified IL10 genetic variant as the moderate risk for CC. In another recent meta-
analysis, it was reported that only IL-10 A1082G SNP was associated with
cervical cancer susceptibility (de Moura et al. 2020).
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7.3.1.6 IL-12
Interleukin-12 (IL-12) is another important proinflammatory cytokine, which serves
as the bridge between the early non-specific immune responses (innate) and second-
ary antigen-specific immune responses (adaptive) and is mainly produced by the
antigen-presenting cells (Del Vecchio et al. 2007). It functions to induce the produc-
tion of interferon-γ (IFN-γ), enhance the cytot oxic activity of natural killer cells,
promote the differentiation of Th1 cells, and inhibit the angiogenesis via production
of antiangiogenic factors (Del Vecchio et al. 2007; Trinchieri et al. 2003). IL-12 is
principally secreted by the activated antigen-presenting cells like dendritic cells,
macrophages, and monocytes.
Structurally IL-12 protein is a dimer of two different subunits –IL-12p35 (35 kD
α-chain) and IL-12p40 (40 kD β-chain), linked via disulfide linkages (Trinchieri
et al. 2003). IL-12p35 and IL-12p40 polypeptides are translated by two distinct
genes located within chromosome 3 (IL-12A; 3q25.33) and chromosome 5 (IL-12B;
5q33.3), respectively (Trinchieri et al. 2003). Due to the varied range of immuno-
logical functions of IL-12, numerous researchers have studied the influences of
IL-12 genetic polymorphisms on susceptibility to various cancers (Tan et al. 2016;
Sun et al. 2015a, b) including cervical cancer (Zeng et al. 2017; Chang et al. 2015;
Chen et al. 2012a, b; Zhou et al. 2012a, b). About four common genetic variants of
IL-12 gene have been identified which include - 3’UTR A > C (1188A > C;
rs3212227), 3’UTR G > A (277G > A; rs568408), IVS2T > A (798T > A;
rs582054), and 5’UTR T > G (564T > G; rs2243115). All of the four SNPs have
been found to affect the IL-12 gene expres sion ability resulting in defective protein
synthesis, and consequently lead to carcinogenesis.
In cervical cancer, an early meta-analysis by Zhou et al. (2012a, b) found that
IL-12 3’UTR A
> C (rs3212227) SNP was significantly associated with the
increased overall risk of cancers [OR ¼ 1.14, 95% CI: 1.02–1.27]. Additionally,
they also reported that the 3’UTR A > C (rs3212227) SNP was associated with
increased risk of cervical and nasopharyngeal cancers in the subgroups of Asians.
However, they did not find any association for other SNPs: IL-12 3’UTR G > A
(rs568408), IVS2 T > A (rs582054), and 5’UTR T > G (rs2243115). In their meta-
analysis Zeng et al. (2017) also reported that IL-12 3’UTR G > A (rs568408) SNP
was responsible for the increased cervical cancer risk and overall cancer risk among
Caucasians. The meta-analysis by Chang et al. (2015) reported that IL-12
3’UTR +1188 (rs3212227) polymorphism was not associated with risk of CC
[OR ¼ 1.09, 95% CI: 0.88 ~ 1.35]. Chen et al. (2012a, b) reported a significant
association between IL-12B rs3212227 SNP and overall cancer risk [OR ¼ 1.32,
95% CI ¼ 1.06–1.63], while as in stratified analysis they reported a significant
increased risk of CC [OR ¼ 1.34, 95% CI ¼ 1.04–1.73 ].
7.3.1.7 HLA
Human leukocyte antigen (HLA) genes are a part of 7.6Mbps long major histocom-
patibility complex (MHC) cluster, mapped at chromosome 6 (6p21.31) in humans
and encodes a wide variety of surface proteins that play crucial role in the immune
response to pathogens (de Araujo et al. 2009; Horton et al. 2004). HLA comprises a
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family of two types of genes—Class I and Class II genes both of which are different
in structure as well as in funct ion (Klein and Sato 2000) [Fig. 7.5].
The HLA class I genes code for the α-polypeptide chain of the class I molecule,
which has five functional domains: two peptide-binding domains (α1 and α2), one
immunoglobulin-like domain (α3), the transmembrane region (α4), and the cyto-
plasmic domain (α5). The HLA class I β-chain referred to as beta2-microglobulin is
a product of distinct gene present on chromosome 15 (Horton et al. 2004; Klein and
Sato 2000). Almost all somatic cells are known to have capability to express Class I
HLA genes, but the levels of expression do vary in different tissues. Class II HLA
genes are translated to α and β polypeptide chains which make up the structure of the
class II molecules [Fig. 7.6]. Each of the class II α and β chains consists of four
structural domains: the peptide-binding domain (α1orβ1), the immunoglobulin-like
domain (α2orβ2), the transmembrane domain, and the cytoplasm facing domain.
Class II genes are normally expressed by a subgroup of immune cells that includes
B-cells, activated T cells, macrophages, dendritic cells, and thymic epithelial cells
(de Araujo et al. 2009; Horton et al. 2004; Klein and Sato 2000).
The HLA system is known to play a pivotal role for the host immune response by
mediating antigen presentation to the effector cells. There is a huge variability in the
structure of the HLA molecules especially within the peptide-binding regions which
in turn determine the antigen repertoire capable of binding to each HLA molecule for
their display to the T cells for immune responses (de Araujo et al. 2009; Klein and
Sato 2000). For the successful and efficient activation of T-cell response the
interactions between HLA-peptide complex and the T-cell receptors is a critical
step. Thus, the genetic variation in the peptide-binding region of the HLA molecules
does affect their ability to bind and present the same to the immune system for the
Fig. 7.5 Location and organization of the HLA complex on chromosome 6. The class II HLA gene
loci on chromosome 6 are designated by three letters: the first (D) which indicates the class of gene,
the second letter (M, O, P, Q, or R) represents the family, and the third letter (A or B) for the chain
(α or β, respectively)
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effective response specially to initiate a cell-mediated immune response to HPV
infection (de Araujo et al. 2009). Class II genes (DR, DQ, and DP) play a critical role
as they are particularly responsible for exposing and presenting the processed viral
peptides to the immune system, including that of HPV (Xu et al. 2020; Horton et al.
2004).
Numerous molecular and epidemiological studies especially meta-analysis have
investigated the relationship of HLA genetic variations and cervical cancer risk
(Xu et al. 2020; Brown and Leo 2019; de Araujo Souza et al. 2003; Kamiza et al.
2020; Cheng et al. 2018 ; Zhang et al. 2015; Wei et al. 2014). Numerous worldwide
studies have identified that many HLA alleles like HLA-DPB102:02, DPB103:01,
DPB104:02, DPB105:01, DPB113:01, rs9277535 (DPB1), rs4282438 (DPB2),
rs3117027 (DPB2), and rs3077 (DPA1) to be significantly associated with the risk
of CC (Cheng et al. 2018).
Kamiza et al. (2020), in their meta-analysis on 13DRB1 family alleles, report ed
that in the Asian population, the HLA-DRB1*07:01, DRB1*09, and DRB1*15:02
were associated with an increased risk of CC, while as HLA -DRB1*04:06,
DRB1*12:02 and DRB1*13:02 were reported to be associated with decreased risk
of CC. However, in Caucasians it was found that HLA-DRB1*04:01, DRB1*04:03,
DRB1*11, and DRB1*15:01 were associated with an increased CC risk, while as
HLA-DRB1*13, DRB1*13: 01, and DRB1*13:02 had a protective effect on cancer
risk. Additionally, in the Hispanic or Latin American population,
HLA-DRB1*15:01 and DRB1*15:03 increased the risk of CC, whereas DRB1*13
and DRB1*13:02 had a protective effect.
Cheng et al. (2018), in their meta-analysis on 11 HLA-DP alleles, reported that
HLA-DPB1*03:01 was significantly associated with an increased risk of CC
Fig. 7.6 Structure of HLA class I and class II molecules
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[OR ¼ 1.252, 95%CI: 1.116–1.403], while HLA-DPB1*04:02 and HLA-DP
rs3117027 G allele were significantly associated with a decreased risk, and
HLA-DP rs9277535 G allele was significantly associated with a decreased risk of
CC in Asia [OR ¼ 0.802, 95%CI: 0.753–0.855, P ¼ 0.001]. In their meta-analysis to
investigate the role of HLA-DQB1 alleles on cervical cancer risk, Zhang et al. (2015)
reported that the HLA-DQB1 alleles may contribute to genetic susceptibility to CC.
They found that HLADQB1*02, HLADQB1*03, and HLADQB1*0603 decreased
the risk of cervical cancer significantly, while as DQB1*05, HLADQB1*0301, and
HLADQB1*0402 had a higher risk of CC. Similarly, Zhang et al. (2014a, b) had
previously identified HLA DQB1 as the high risk and HLA DQA1 as weaker risk
genetic variants for CC susceptibility.
7.3.2 Polymorphisms in Pathogen Response Genes
Toll-like receptors (TLRs) are the pivotal constituents of innate and adaptive
immune system which are known to initiate inflammatory response (Akira et al.
2001). TLRs play a significant role in regulating the reactions and mechanisms
involved in in flammation and activation of immune responses to foreign pathogens
for their elimination. The foreign pathogen can be bacteria, fungi, and viruses as well
as cancer debris (Yang et al. 2017; Wang et al. 2008; Werling and Jungi 2003; Akira
et al. 2001). TLRs are type I transmembrane proteins that are normally anchored
within the cellular bio-membranes, be it extracellular membrane or intracellular
organelle membrane of lysosomes or endosomes, characterized by unique leucine-
rich repeats in the interaction domain. They recognize pathogen-associated molecu-
lar patterns (PAMPs) which are the main structural protein motifs present in the
pathogenic organisms (Mogensen 2009; Wang et al. 2008).
TLRs are known to possess high genomic conservation between humans and
mice and around 11 human TLRs and 13 murine TLRs have been characterized so
far [Table 7.4], four have been identified to play an important role in the cervical
cancer risk—TLR2, TLR3, TLR4, and TLR 9 (Pandey et al. 2019; Mehta et al.
Table 7.4 TLRs and their essential ligands
TLRs Ligands
TLR1/2 Triacylated lipopeptides
TLR2 Mycoplasma, non-lipopeptidic PAMPs from various pathogens
TLR2/6 Diacylated lipopeptides
TLR3/7/8 Viruses or bacteria mainly in the nucleic acid
TLR4 Lipopolysaccharide (LPS) of gram-negative bacteria
TLR5 Bacterial flagella
TLR9 Unmethylated DNA of bacteria or virus
TLR10 Remain unidentified
TLR11 T. gondii profilin and uropathogenic Escherichia coli
Abbreviations: PAMP pathogen-associated molecular pattern, TLR toll-like receptors
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2017a, b; Zidi et al. 2014). The TLR genes are found throughout the human genome:
the genes encoding TLR1 and TLR6 are found in chromosome 4p14, TLR2 and
TLR3 have been mapped to 4p31.3-q35, TL4 to 9q32-q33, TLR5 to 1q33.3-q42,
TLR7 and TLR8 to Xp22 and TLR9 to 3p21.3 (Akira et al. 2001).
7.3.2.1 TLR2
TLR2 plays a central role in recognizing the foreign pathogens especially gram-
positive bacteria, listeria, and yeasts. It is necessary for the cellular response to
lipopolysaccharide (LPS), peptidoglycan (PGN), mycoplasma lipopeptide
macrophage-activating lipopeptide-2 (MALP-2), and lipoarabinomannan (glyco-
lipid of mycobacterium tuberculosis) (Yang et al. 2017; Werling and Jungi 2003;
Akira et al. 2001). TLR2 has also been found to play a critical role in detecting the
various viral pathogens as well (Mehta et al. 2017a, b; Nischalke et al. 2012).
Numerous SNPs of TLR2 have been reported to be correlated with cancer
susceptibility including cervical cancer in some genetic studies (Yang et al. 2017 ;
Zidi et al. 2014, 2016;Bietal.2014;Kutikhin2011; El-Omar et al. 2008). In cervical
cancer three important SNPs which have been exhaustively studied in various geo-
graphical areas of world are: TLR2 + T597C (rs3804099), TLR2 + C1350T
(rs3804100) and TLR2G2477A (R753Q, rs5743708) (Pandey et al. 2009, 2019).
A recent meta-analysis reported that TLR2 + T597C (rs3804099) was associated
with the reduced risk of cancer in general population (Gao et al. 2019). Yang et al.
(2013) in their meta-analysis did also report that TLR2 + T597C (rs3804099),
TLR2 + C1350T (rs3804100), and TLR2G2477A (R753Q, rs5743708) SNPs were
not reported to be associated with cancer risk.
7.3.2.2 TLR3
TLR3 is a unique receptor in the family of toll-like receptors in being able to
recognize the double-stranded DNA (ds-DNA) derived from the cytopathic viruses
(Mehta et al. 2017a, b; Werling and Jungi 2003).
One important genetic polymorphism reported for TLR3 is the non-synonymous
SNP—TLR3 C1377T (rs3775290) located within exon 4 of TLR3 gene (4q35.1).
This SNP alters the TLR3 ectodomain causing impairment of its functions and hence
negatively altering the interaction of ligand with receptor (Sawhney and Visvanathan
2011; Werling and Jungi 2003).
The heterozygous CT genotype of TLR3 C1377T SNP is demonstrated to be
significantly associated with the chronic HCV infection accentuating its role in viral
pathogenesis and evoking of response to viral ds-DNA (Mosaad et al. 2019; Jiang
et al. 2008). Zidi et al. (2016) have also reported that TLR3 C1377T SNP to be
associated with the modification of risk of CC because of the tobacco usage;
however, Pandey et al. (2011) reported contradictory results and suggested only a
marginal role of TLR 3 SNP in CC suscep tibility.
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7.3.2.3 TLR4
TLR4 mimics the role of TLR2 in recognizing the lipopolysaccharide (LPS)
molecules from the gram-negative bacteria and virus particles (Mehta et al.
2017a, b; Long et al. 2014; Werling and Jungi 2003).
The TLR4 gene consists of four exons located on the long arm of chromosome
9 (9q33.1). Two important non-synonymous SNPs have been reported—TLR4
A896G (Asp299Gly, rs4986790) and TLR4 C1196T (Thr399Ile, rs4986791), both
located on the fourth exon of the TLR4 gene. All of the said SNPs are known to
cause a structural modification in the extracellular domain of the TLR4 receptor and
have been demonstrated to be associated with the increased susceptibility to viral or
bacterial infection (Kutikhin 2011; El-Omar et al. 2008; Lorenz et al. 2001).
Recently, Long et al. (2014) demonstrated that TLR4 A896G but not TLR4
C1196T SNP caused an impaired responsiveness of TLR4 to LPS and the
corresponding activation of NF-κB. The cells expressing TLR4 with A896G but
not C1196T SNP were reported to produce significantly less IL-8 cytokine after its
stimulation by LPS. Pandey et al. (2009) reported that TLR4 C1196T polymorphism
was associated with stage II CC. Additionally, both TLR4 A896G and TLR4
C1196T SNPs showed a positive association with HPV 16/18 infection, tumor
progression and hence thereby with risk of CC (Pandey et al. 2019). TLR 4 together
with other TLR gene polymorphisms has also been demonstrated to be involved in
the modification of the risk of CC together with the usage of tobacco (Zidi et al.
2016). Chauhan et al. (2019) also did implicate the TLR4 haplotypes with the risk of
cervicitis in their meta-analysis.
7.3.2.4 TLR9
TLR9 is a special receptor which can recognize unmethylated CpG areas present in
bacteria and viruses. It has been reported that HR-HPV16 derived E6 and E7
proteins are able to directly suppress the immune response by a host cell by
amending the TLR9 transcript. These proteins interact with the regulator sequence
present within the 2 kb upstream region of TLR9 gene to control its expression
(Hassan et al. 2007). Thus, it is hypothesized that genetic variation especially SNPs
which affect the promoter region of TLR9 gene may play a role in modulating the
risk for CC.
The gene coding for TLR9 receptor is mapped to chromosome 3p21.3, a region
which is often deleted in various human cancers (Chuang and Ulevitch 2000). It has
been reported to possess at least 20 SNPs within its sequence but only two of
these have been exhaustively studied in the CC which are -TLR9 -T1486C
(rs187084) and G2848A (rs352140) (Chen et al. 2012a, b).
In one of the seminal studies, Chen et al. (2012a, b) demonstrated that for TLR9
-T1486C SNP, heterozygous TC genotype is significantly linked with increased CC
risk [OR ¼ 1.28, 95% CI ¼ 1.01–1.62] in comparison with homozygous TT
genotype. Pandey et al. (2011) in their study had demonstrated that the AA genotype
of TLR9 G2848A SNP showed borderline significance with the increased risk for
advanced CC stages [OR ¼ 2.63, 95%CI ¼ 0.99–7.01; P ¼ 0.053] (III/IV) in
comparison with the e arly stages (I/II). In contrast, Zidi et al. (2016) reported no
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significant association of TLR9 G2848A SNP with the clinical stages of CC but they
did report that this SNP was able to modulate the CC risk associated wi th the usage
of tobacco and the menopausal status among cases together with TLR2, TLR3,
TLR4 SNPs. In a recent report by Pandey et al. (2019), it was observed that TLR9
-T1486C SNP had an association with HR-HPV 16/18 infection and both TLR9
-T1486C SNP and TLR9 G2848A SNP were associated with cancer’s early stage.
Similar results were also reported by Roszak et al. (2012).
7.3.3 Polymorphisms in Apoptosis Related Genes
Apoptosis is a well-regulated cell suicide mechanism, which is needed for the
elimination of the unnecessary and damaged cells in an individual coupled with its
critical role in morphogenesis and cellular turnover. The process is tightly controlled
by numerous genes for maintenance of the viable functionality of the individual
(Vermeulen et al. 2005). Apoptosis, also referred to as the programmed cell death is
identified by the typical changes in the morphology of the cell which include
blebbing of plasma membrane, shrinkage of cell’s volume, nuclear membrane
dissolution, chromatin condensation and fragmentation. Apoptosis process can
further be intrinsic or extrinsic depending upon the initiating signals that arise
from inside or outside of the cell (Schultz and Harrington 2003) [Fig. 7.7].
The central prote ins which play role in the apoptosis are the effector proteins
called caspases. Caspases are functionally proteases which belong to a family of
cysteine-dependent aspartate-directed proteases that get activated by different
ligands to cleave a larger subset of intracellular proteins to mediate cell suicide by
apoptosis (Vermeulen et al. 2005). The caspase gene family contains 11 human
members which are categorized into three groups. Group 1 includes three caspases:
1, 4, and 5; all of which play role in regulation of inflammation. Group 2 also
includes three caspases: 2, 3, and 7; while group 3 includes four caspases (6, 8,
9, and 10), all of which are involved in regulating the actual apoptosis cascade.
Caspases which play role in apoptosis are further subclassified into two types based
on their mechanism of action a) initiator caspases (8 and 9) or executioner caspases
(3, 6, and 7) (McIlw ain et al. 2013, 2015).
Among the numerous genes which regulate the apoptosis process are the genes
for receptors [FAS-FASL, Toll-like receptors (TLRs)], BCL2 gene family,
DNA-protein kinase (DNA-PK), cell cycle regulators [e.g., pRb, MDM2,
CDKN1], transcription factors (e.g. p53, NF-κB), and cell signaling proteins [e.g.,
Raf, protein kinase B (PKB)] (Vermeulen et al. 2005; McIlwain et al. 2013, 2015).
Genetic variation of the genes involved in the apoptosis mechanism has been
explored very exhaustively and many regulatory genes have been found to be
associated with the susceptibility to various cancers, because of their capacity in
dysregulating the programmed cell death (Vermeulen et al. 2005 ; Schultz and
Harrington 2003 ). Usually the failure of apoptosis leads to the decreased ability of
an individual to eliminate defective cells with damaged DNA which in turn
facilitates the accumulation of somatic mutations, and hence contributing to tumor
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Fig. 7.7 The two main pathways of apoptosis
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