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initiation, progression, and metastasis (Evan and Vousden 2001; Lowe and Lin
2000).
7.3.3.1 FAS
Fas receptor (also known as CD95 or Apo-1) is the apoptotic death receptor for
FasL, is a type I membrane protein which functions as one of the important members
of tumor necrosis factor (TNF) receptor superfamily (Nagata 1997). FAS gene is
located on chromosome 10q24.1, consists of nine exons and eight introns (Mehta
et al. 2017a, b; Tan and Ankathil 2015 ). The interaction of Fas with its ligand (FasL)
is the initial trigger for the activation of signal cascade which eventually leads to
apoptosis, via an extrinsic pathway (Nagata 1997). Numerous molecular studies
have previously reported the downregulation of Fas expression and/or up-regulation
of FasL expression in many human cancers (Rabinowich et al. 1998; Crnogorac-
Jurcevic et al. 2001). While on one side this helps the damaged cell evade the
elimination via anti-tumor immune responses and on the other side increases the
ability of damaged cells to counterattack the immune system, thereby playing critical
roles in carcinogenesis mechanisms (Vermeulen et al. 2005; Evan and Vousden
2001; Lowe and Lin 2000 ).
For the promoter region of FAS gene, two SNPs have been studied extensively
because of their association with CC susceptibility, they are FAS -A670G
(rs1800682) and -G1377A SNP(rs2234767) (Mehta et al. 2017a, b; Tan and
Ankathil 2015; Nunobiki et al. 2011; Lai et al. 2003, 2005). Both of these SNPs
have been found to affect the Sp1 and STAT1 transcription factor binding sites
resulting in the diminished promoter activity hampering the expression of the gene
and consequently leading to decreased FAS expression (Kanemitsu et al. 2002;
Nunobiki et al. 2011). FAS -A670G SNP is mapped within the interferon gamma
activation sequence (GAS) of the gene that serves as a binding site for STAT1
transcription factor while FAS -G1377A SNP is located within the binding site of
SP1 transcription factor (Kanemitsu et al. 2002; Sibley et al. 2003).
For the FAS -G670A SNP a varying association with the cancer in general and
cervical cancer in particular has been reported (Xu et al. 2014). Xu et al. (2014)
reported an association of FAS -G670A SNP with the overall risk of cancer in a
homozygous model, same was the report published by Nunobiki et al. (2011)in
which association of this SNP was found to be with the CC risk and HPV infection
type. Lai et al. (2003) also reported the association of FAS -G670A SNP with the
cervical carcinogenesis. However, a meta-analysis by Shen et al. (2013) has reported
that FAS -G670A SNP was not associated with the susceptibility to CC for all four
models of inheritance [OR varying between 0.92 to 0.97] and for the ethnicity as
well (both Caucasians and Asians). Wang et al. (2014) also reported the similar
results for the FAS -G1377A SNP in both Asians and Africans.
7.3.3.2 FASL
Fas ligand (FasL) is another important part of the Fas signaling of apoptosis. This
serves as the ligand for the binding to the Fas receptor and is a product of FASL gene
located on chromosome 1q24.3 (Mehta et al. 2017a, b; Tan and Ankathil 2015).
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Two SNPs of FasL gene have been reported to increase the susceptibility to
cancers: FasL IVS2nt-124 A > G (rs5030772) and FasL -T844C (rs763110) (Nagata
1997; Lai et al. 2005). Out of these two, FasL -T844C SNP has been studied
extensively for its association with CC (Xu et al. 2014). FASL -T844C SNP is
located within a presumed binding motif for CAAT/enhancer-binding protein
(C/EBPβ); the two iso-forms have different affinities for binding to the C/EBP β
which affects the functional expression of the gene and hence FASL-mediated
signaling in lymphocytes (Nagata 1997; Rabinowich et al. 1998).
Wang et al. (2014) reported that FasL T844C SNP was not associated with the
susceptibility to CC in both Asians and Africans. Similar results were also reported
by other two meta-analyses separately (Xu et al. 2014; Zhu et al. 2014).
7.3.3.3 CASP8
As mentioned above, caspases are the main regulative and executive drivers of the
apoptosis mechanism. Among all caspases, caspase 8 plays a central role in driving
the extrinsic apoptosis pathway. Caspase 8 is the first one to be recrui ted after the
binding of the external FasL (CD95-L) with the Fas receptors on the surface of
lymphocytes towards the FAS-associated death domain (FADD) or TNFR-
associated death domain (TRADD). Recruitment of caspase 8 resul ts in the dimer-
ization and then its spontaneous activation. Activated caspase 8 then either initiates
apoptosis directly by cleaving and thereby activating executioner caspases (3, 6,
7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce
efficient cell death. (McIlwain et al. 2013, 2015).
Caspase 8 protein is coded by the CASP8 gene, located on chromosome 2q33.1
and consists of 11 exons spanning approximately 30 kb (Grenet et al. 1999). CASP8
gene is one of the highly polymorphic genes and is reported to contain around
500 genetic polymorphisms in its sequence (Cai et al. 2017). Of all the
polymorphisms in CASP8 gene, 652 6 N ins/del polymorphism (/CTTACT,
rs3834129) is the most studied and reported upon. It is a six-nucleotide insertion/
deletion variant located in the CASP8 promoter region, which has been shown to
lead to decreased CASP8 expression (Sun et al. 2007). The decreased expression and
hence activity of caspase 8 affect the extrinsic apoptotic pathways drastically which
results in the compromised immune surveillance of the tumor cell, thereby affecting
carcinogenesis development and progression (Hashemi et al. 2012).
In one of the recent meta-analyses, it is reported that CASP8–652 6 N ins/del
polymorphism was associated with decreased overall cancer risk including that
of CC, both in Asian and Caucasian populations (Cai et al. 2017). Furthermore,
another meta-analysis reported CASP8 rs1045485 polymorphism was not associated
at all with the CC susceptibility (Hashemi et al. 2020).
7.3.3.4 TP53
The p53 protein is one of the critical tumor suppressors present in the cell, which is
responsible for maintaining the integrity and functionality of the genome. p53
protein plays a central role in inducing cell cycle arrest, apoptosis, or DNA damage
repair, negatively regulating the cell cycle (Berchuck et al. 1994). p53 plays a crucial
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role in the intrinsic pathway of apoptosis, as it plays a pivotal role of transcriptional
activator for numerous pro-apoptotic genes like Bax, Noxa, Puma, and Bid which
are expressed in response to the irreparable damage to DNA (Vermeulen et al. 2005;
Evan and Vousden 2001; Lowe and Lin 2000). Additionally, p53 is known to induce
the transcription of FAS gene and promotes the trafficking of Fas proteins out of the
Golgi complex, which does establish that p53 can also modify apoptosis mechanism
via the activation of the extrinsic pathway (Bennett et al. 1998).
TP53, being a principal tumor suppressor gene is one of the most frequently
mutated genes in all types of human cancers (Whibley et al. 2009). It is found on
chromosome 17p13.1, is of 19 kb in length, and consists of 11 exons encoding a
transcript of 2629 bp and a p53-protein of 393 amino acids (Bojesen and
Nordestgaard 2008). As described in the previous chapters, TP53 possesses numer-
ous polymorphisms of which two non-synonymous SNPs are important, because of
their ability to result in the change in structure of protein which affects its tumor
suppressing capacity. These SNPs are located at codon 47 (P47S; rs1800371) and
codon 72 (P72R; rs1042522) of TP53 gene in exon 4 (Pietsch et al. 2006; Murphy
2006).
In cervical cancer, as already described above one of the major arms of mecha-
nism of HPV pathogenesis and tumorigenesis is via forced induction of p53 degra-
dation through the activation of E6/E6AP complex, making TP53 a possible
candidate gene in cancer (Vermeulen et al. 2005; Evan and Vousden 2001; Lowe
and Lin 2000). The TP53 Pro72Arg polymorphism has been envisaged to make p53
protein more vulnerable to E6/E6AP-mediated degradation by about seven times and
hence can influence the susceptibility to cervical cancer especially in individuals
with homozygous Arg-72 genotype (Storey et al. 1998; Habbous et al. 2012; Sousa
et al. 2011). It was reported that Arg variant (Arg72) of p53 protein binds to the high-
risk HPV E6 protein with greater efficiency than the Pro variant and there also occurr
differences in the affinity between p53 and endogenous transcriptional elements with
the Arg variant (Habbous et al. 2012; Sousa et al. 2011).
In the past two decades considerable molecular and epidemiological studies have
focused on the association of p53 polymorphisms with the risk of CC. In a recent
meta-analysis, Habbouset al. (2012) reported that for individuals with HPV infection
p53 Arg allele (rs1042522) was significantly associated with the risk of CC [OR:
1.37; 95% CI: 1.15–1.62; P < 0.001]. Zhou et al. (2012a, b) in their meta-analysis
found that Pro/Pro genotype was associated with increased risk of CC under the
heterozygous model (Pro/Pro vs. Arg/Pro: OR ¼ 1.25, 95%CI: 1.02–1.53,
P ¼ 0.005). Furthermore, the subgroup analysis showed that the Pro/Pro genotype
and Pro carrier to be significantly associated with increased CC risk among Indian
population, but not among Korean, Japanese, and Chinese.
7.3.3.5 MDM2
Mouse double minute-2 homolog (Mdm2) shares the intricate relationship with p53
as both interact dynamically with each other via an autor egulatory loop in which p53
functionality is negatively regulated by Mdm2. MDM2 gene which encodes Mdm2
protein located on chromosome 12q13–15 is itself transcriptionally inducible by p53
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(Ortiz et al. 2018; Saadatzadeh et al. 2017; Bieging et al. 2014). Mdm2 is also known
to contain E3 ubiquitin ligase activity via which it degrades the inactivated p53
protein through ubiquitination and proteasomal activity (Saadatzadeh et al. 2017).
One of the important genetic polymorphisms that have been reported for the
MDM2 gene is the SNP present in its first intron - T309G (rs2279744) at position
309 (Bond et al. 2004). This has been reported to enhance the binding affinity of the
Sp1 transcription factor to its consensus sequenc e in the MDM2 promoter and hence
results in the elevated levels of MDM2 in cells eventually decreasing the tumor
suppressing activity of p53 protein (Ortiz et al. 2018; Saadatzadeh et al. 2017;
Bieging et al. 2014).
Numerous meta-analyses on the role of MDM2 T309G SNP in modulation of CC
risk have been reported but with conflicting outcomes (Tan and Ankathil 2015; Zhuo
et al. 2014; Singhal et al. 2013; Jiang et al. 2011; Nunobiki et al. 2010 ; Hu et al.
2010). Zhuo et al. (2014) had reported a significant association between MDM2
T309G SNP and CC risk [GG vs TT: OR ¼ 1.31; 95% CI ¼ 0.55–3.13; Dominant
model: OR ¼ 1.22; 95% CI ¼ 0.65–2.31; Recessive model: OR ¼ 1.45; 95%
CI ¼ 0.79–2.65]. They concluded that homozygous GG alleles of MDM2 T309G
SNP might be a risk factor for CC especially among Asians. Zhang et al. (2018)
reported a significant associ ation of MDM2 SNP with the risk of gynecological
cancers but they didn’t find any notable association between MDM2 T309G SNP
and CC risk.
7.3.4 Polymorphisms in Antigen-Processing Genes
The antigen-processi ng and presentation machinery (APM) is one of the intricate
assemblies of multiple molecular species and proteins all of which work together for
the generation of antigens to be presented on the surface of antigen-presenting cell in
conjunction with the human leucocyte antigen (HLA) for the recognition and hence
activation of cytotoxic T lymphocytes (Leone et al. 2013). As already described
previously HLA are of two main types: Type I and Type II (Klein and Sato 2000). In
order to express the peptides bound to HLA molecules on the surface of antigen-
presenting cell, APM functions to perform four main tasks: (1) peptide generation
and trimming; (2) peptide transport; (3) assembly of the MHC class I loading
complex; and (4) antigen presentation (Leone et al. 2013; Blum et al. 2013).
Furthermore, depending upon the source, the peptides derived from proteins
degraded by the lysosomal pathway are primarily presented by MHC class II
molecules, whereas the peptides generated by the ubiquitin-proteasome pathway
are presented by MHC class I molecules (Blum et al. 2013; Yewdell 2001).
To function effectively APM itself is made up of many kinds of proteins
performing a specific function in the antigen processing. The main components of
the APM are: multimeric protein complex proteasome, low molecular-weight
proteins (LMP), transporter associated with antigen presentations (TAP), endoplas-
mic reticulum aminopeptidase associated with antigen presentations (ERAP) (Leone
et al. 2013).
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The proteasome is a multimeric protein complex found in both the cytosol and
nucleus and does the function of breaking down the polyubiquitinated proteins to the
potent antigens. LMP 2 and 7 are involved in generation of peptides from intracel-
lular proteins. The peptides generated within the cytosol are then actively transported
into the ER by the TAP. TAP forms a heterodimeric complex of the two half-
transporters, TAP1 and TAP2. TAP1 and TAP2 are involved in transporting pep-
tides (8–12 residues) from the cytosol to the endoplasmic reticulum (ER) via its
transmembrane pore in the ER membrane whose opening and closing depends on
ATP binding and hydrolysis, respectively (Lankat-Buttgereit and Tampé 2002;
Schumacher et al. 1994). Once in ER, the peptides undergo further trimming by
ERAP1 and ERAP2 to fit into the groove of the MHC class I molecules. ERAP1 is
considered a “molecular ruler” because of its substrate preference and ability to trim
peptides of 9–16 residues specifically (Chang et al. 2005). In addition many more
proteins including tapasin, calnexin, calreticulin, and ERp57 do also contribute to
the APM (Blum et al. 2013) [Fig. 7.8].
Numerous genetic polymorphisms affecting various genes encodi ng APM
components have been found to be associated with the susceptibility to CC (Mehta
et al. 2007, 2017a, b). The important genes of the APM, which have been studied for
the role played by their genetic variation are discussed below.
7.3.4.1 LMP
The low-molecular-weight polypeptide (LMP) system plays a pivotal role in the
recognition of intracellular infection—a critical part in immunological surveillance
in humans via MHC-Class I and cytotoxic T-lymphocyte (CTL) pathway (Leone
et al. 2013). The gene coding for both types of LMPs (LMP2/7) is in the MHC class
II region of human chromosome 6 (6p21.3) (Monaco 1992).
LMP2 and LMP7 make up two critical subunits of proteasome that play a role in
the degradation of cytosolic proteins and result in the production of peptides for
presentation by HLA system (Blum et al. 2013; Schumacher et al. 1994). Several
studies have reported on the genetic polymorphisms of LMP genes especially LMP2
A60G (Arg > His, rs17587) and LMP7 C145A (Gln > Lys, rs2071543) which result
in the functional alteration in the proteins resulting in the impaired capacity of APM
of the cells. Thus, these genetic variations have been reported to be associated with
the development and progression of various cancers (Wu et al. 2017; Ma et al. 2015;
Mehta et al. 2007, 2015, 2017a, b; Song et al. 2014; Cao et al. 2006).
In a recent meta-analysis, Wu et al. (2017) reported that the SNPs of LMPs
(rs17587 and rs2071543) were associated with an increased risk of cancer in the both
recessive and homozygote models. However, after stratification of data the risk was
found to be significant only for Asian population. Mandal et al. (2017) demonstrated
in their report that LMP7 (rs2071543) plays a significant role in incre asing cancer
risk by two folds [AA vs CC: OR ¼ 2.602, 95% CI ¼ 1.780 to 3.803; p ¼ 0.001] in
general and in particular Asian population but not in Caucasians, and hence could be
useful as a prognostic marker for early cancer predisposition.
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7.3.4.2 Tap
Transporter associated with antigen presentation (TAP) plays a crucial role in the
second stage of antigen processing. This involves the ATP dependent transport of
newly generated peptides from the cytosol to the endoplasmic reticulum (ER) for
further processing or trimming and subsequent expression or presentation on the
surface of the cell (Blum et al. 2013; Schuma cher et al. 1994; Engelhard 1994). TAP
functions as a heterodimer, which consists of two transmembrane domain-containing
subunits, TAP1 and TAP2. TAP1 and TAP2 also possess motif for binding of ATP
(Engelhard 1994; Lankat-Buttgereit and Tampé 2002).
The genes, which encode TAP1 and TAP2 proteins, are located in the short arm
of human chromosome 6 (6p21.32). A number of genetic variations including
Fig. 7.8 The antigen processing of MHC class I peptides. Four main steps in the processing
involve (1) antigen uptake, (2) processing through proteasome, (3) peptide transport and association
with MHC class 1, and (4) expression on surface of cell
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polymorphisms in the form of SNPs have been reported in TAP1 and TAP2 genes.
Of these TAP1 1341 (rs1057141) and TAP1 2254 (rs1135216) polymorphisms in
TAP1 gene and TAP2 1135 (rs1800454), TAP2 1693 (rs2228396) and TAP2 1993
(rs241447) polymorphisms in TAP2 gene have been extensively studied for their
role in modulating the risk of cervical cancer (Praest et al. 2018; Mehta et al.
2017a, b; Natter et al. 2013; Faucz et al. 2000).
Einstein et al. (2009) have reported the association of two TAP1 gene SNPs,
TAP1 I333V and TAP1 D637G with high-grade CIN, however, no such association
has been reported for any TAP2 gene SNPs. Natter et al. (2013) and Kordi
Tamandani (2009) have also reported no such association between TAP gene
SNPs and the risk of CC.
7.3.4.3 ERAP
Endoplasmic reticulum (ER) aminopeptidases (ERAPs) are the third level proteins
involved in the antigen-processing machinery (APM). They are located within the
lumen of the endoplasmic reticulum where they act upon the peptides entering ER
via transporter associated with antigen processing (TAP) and process or trim them to
fit MHC class I proteins, which in turn present these antigens on the surface of the
cell (Blum et al. 2013; Schumacher et al. 1994; Engelhard 1994).
Human ERAPs, ERAP1 and ERAP2 are important members of a subfamily of
M1 zinc metalloproteases known as oxytocinase, which catalyze the trimming of the
N-terminal regions of peptides to make them fit to be loaded onto the HLA Class I
molecules. ERAP1 and ERAP2 are induced by tumor necrosis factor-α (TNF-α) and
interferons (IFNs) including INF-γ and exhibit almost 50% homology with each
other in their sequences (Saulle et al. 2020; Neefjes et al. 2011).
ERAPs function together in a well-coordinated manner and so as not to be
redundant there are marked differences in their enzymatic specificities. ERAP1, a
type II integral membrane protein, has a cleavage preference for peptides, which
contain large hydrophobic amino acids in their C-terminal side and usually acts on
peptides, 9–16 amino acids in length, to generate smaller fragments, 8–9 amino acids
in length, which is optimal to fit MHC class I proteins (Hattori and Tsujimoto 2013).
In comparison, ERAP2 is not a type II integral membrane protein, and has a cleavage
preference for peptides, which contain positive ly charged amino acids, arginine and
lysine, in their N-terminal side. ERAP2 usually acts on peptides shorter in length in
comparison with what ERAP1 can process (Saulle et al. 2020; Hattori and Tsujimoto
2013; Serwold et al. 2001). However, it has been reported that ERAP1 and ERAP2
interact with each other physically in ER and form a functional heterodimer to
modulate each other’s activities (Saveanu et al. 2005).
Two separate genes, which are oriented in opposite direction and located on
chromosome 5, locus 5q15, encode human ERAPs. ERAP1 gene has a length of
47,379 bp and contains 20 exons. ERAP2 gene has a length of 41,438 bp and
contains 19 exons. A number of genetic variations including polymorphisms in the
form of SNPs have been reported in both these genes. More than a dozen intronic
and exonic variations have been reported in ERAP1 gene. However, only two
genetic variations have been reported in ERAP2 gene. Since ERAP1 and ERAP2
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proteins play vital roles in antigen processing and presentation pathways, any
genetic variation which affects their functioning is essentially a prelude to various
immune linked diseases including infectious diseases and cancers (Saulle et al. 2020;
Hattori and Tsujimoto 2013). Yao et al. have reported exhaustively on the role
played by several ERAP SNPs in modulating the susceptibility to various autoim-
mune diseases, infectious diseases, as well as cancer initiation and/or progression.
The downregulation of ERAPs has been reported in cervical cancer and this
downregulation has been associated with initiation and progression of CC
(Compagnone et al. 2019; Stratikos et al. 2014).
In a recent study, Liu et al. (2017) investigated the impact of ERAP1 and ERAP2
variants on HCV chronic infection, and found that the ERAP1 rs26618 polymor-
phism may affect either the enzymatic activity or the structure, leading to alterations
in the HCV antigen presentation pathway, and in turn to increased susceptibility to
this infection. It was also observed that combination of rs26618-C/rs2248374-A on
the two genes also provides a greater risk of susceptibility to HCV chronicity.
Paladini et al. (2018) reported that the presence of a G instead of an A at SNP
rs75862629 in the ERAP2 gene promoter strongly influences the expression of the
two ERAPs with a down-modulation of ERAP2 coupled with a significant higher
expression of ERAP1.
ERAP1 rs2704 4 SNP has been reported to modulate CC risk. The variant form of
rs27044 SNP has been reported to result in a significantly decreased ERAP1 mRNA
expression in comparison with wild form of this SNP (P ¼ 1 10
3
) (Mehta et al.
2007). Another study has reported a significant difference in the frequencies of allelic
and genotypic forms of ERAP1 rs26653 SNP, ERAP1 rs27044 SNP, and ERAP2
rs2287988 SNP between the cervical cancer case and control groups. Furthe r, three
haplotypes involving these genes have been associated with an increased cervical
cancer risk. These include one ERAP1 haplotype, ERAP1-rs27044C-rs30187T-
rs26618T-rs26653G-rs3734016C haplotype and two ERAP2 haplotypes, ERAP2-
rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T, and ERAP2-
rs2549782G-rs2548538A-rs2248374A-rs2287988G-rs1056893T (Li et al. 2020).
7.4 Conclusion
As discussed in this chapter, several polymorphisms in the low penetrance genes
have been reported to be involved in modulating the susceptibility of an individual
towards cervical cancer. However, the expression and function of numerous genes is
affected by the dynamic gene environment interactions. Therefore, large-scale
genome-wide association studies need to be conducted in various populations in
order to understand fully their mutual relationships and to devise the susceptibility
model for cervical cancer, which encompasses most of the populations of the world,
irrespective of their ethnicity or race.
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