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Based on their carcinogenic properties all HPV infection types have been
categorized into two groups—high risk (HR) and low risk (LR). The high-risk
(HR) group includes human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 68, and 59. Of these , HPV type 16 and HPV type 18 have been
reported to be associated with almost 70% of all the cases of CC making them very
high-risk types. The low-risk (LR) group includes HPV type 6 and HPV type 11 and
these have been reported to cause genital warts and cervical lesions (WHO 2020;
CDC 2020; Chan et al. 2019; Crosbie et al. 2013; Munoz et al. 2003; Zur Hausen
2002).
7.1.2 Types, Classification, and Grading
As true for any solid tumor, cervical cancer is categorized into three types—
adenocarcinoma (AC), squamous cell carcinoma (SCC), and small cell carcinoma.
Squamous cell carcinoma constitutes almost 80% of all CC cases whereas adenocar-
cinoma makes up to 20% of all CC cases. Small cell carcinoma is a very rare type
and usually accounts for about less than 3% of all CC cases (CRUK 2020).
The development of cervical cancer takes multiple years and goes through three
observable stages, each varying in severity (cervical intraepithelial neoplasia—CIN
1–3) (NCI 2020).
Table 7.1 Types of human papillomavirus (HPV) with various disease associations
Genital lesion
HPV type
Highly prevalent Less prevalent
Plantar or foot warts 1, 2 4, 63
Common warts
(Verruca vulgaris)
2, 1, 7 4, 26, 27, 29, 41, 57, 65, 77, 1, 3, 4, 10, 28
Flat warts (Verruca
plana)
3, 10 26, 27, 28, 38, 41, 49, 75, 76
Epidermodysplasia
Verruciformis
2, 3, 10, 5, 8,
9, 12, 14, 15, 17
19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 50
Focal epithelial
hyperplasia of neck
13, 32
Conjunctival
papillomas/carcinomas
6, 11, 16
Condylomata
acuminate (genital
warts)
6, 11 42,44,51,53,83
Intraepithelial
neoplasias
16 6,11,18,26,30,31,33,34,35,39,40,42,43,
45,51,52,53,54,55,56,57,58,59,61,62,64,
66,67,68,69,70,71,73,74,79,81,82,83,84
Cervical and other
cancers
16,18 31,33,35,39,45,51,52,54,56, 58,59,66,68,69
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CIN1: Also known as low-grade or mild dysplasia, it is the first stage of disease,
which is characterized by the presence of slightly abnormal cells on the surface of
the cervix. Over 70–80% of CIN1 lesions regress without any intervention or
become undetectable (Insinga et al. 2009).
CIN2: Also known as high-grade or moderate dysplasia, it is the second stage of
disease, which is characterized by the presence of moderately abnormal cells on
the surface of the cervix. It is generally caused by HR-HPV and is detectable only
when the cervical biopsy is performed. For CIN2 stage, an annual regression rate
ranges from 15 to 23%, with almost 55% regressing by 4–6 years. Only 2% of
CIN2 lesions are known to advance to CIN3 within a period of 4–6 years
(Moscicki et al. 2010).
CIN3: It is the third and final stage of disease, which is characterized by the presence
of severely abnormal cells lining the surface of cervical wall. However, CIN3
stage is not considered as cancer but only as a true precancerous lesion, which can
progress into an invasive cancer and this progression into cancer occurs at a rate
of 0.2–4% per year. If left untreated, CIN3 stage has a 30% probability of
developing into an invasive cancer over a period of 30 years. If treated, CIN3
stage has only 1% probability of developing into an invasive cancer over the same
period (Chan et al. 2019; Moscicki et al. 2010). The period needed for the
development of CC from the time of HPV infection is usually about 2 decades;
therefore, a quick progression of CC is rarely seen.
According to criteria proposed by the International Federation of Gynecology and
Obstetrics—FIGO 2018 (Salib et al. 2020; Saleh et al. 2020), cervical cancer is
divided into four stages (Table 7.2). The diagnosis is done after a careful histological
resection and examination of the specimen with the help of suitable imaging, biopsy
of the lymph nodes, or surgical assessment of the extent of tumor (Bhatla et al. 2019;
Tsikouras et al. 2016).
7.2 Genetics of Cervical Cancer
As discussed earlier, the single most pivotal risk factor for the initiation and
progression of cervical cancer is the infection by HPV; therefore, the transition of
CC from the foundation of HPV infection to preinvasive lesions and finally to an
invasive cancer usually takes decades (Tjalma et al. 2004). However, a well-defined
molecular mechanism, which would explain the initiation of an incessant infection
by HPV, which in turn results in the initiation and progression to CC, is still not fully
established. However, numerous pathways have been found to be involved in the
carcinogenesis mechanism and various pathways, which are of greatest importance
in this regard, include the immune response pathways, DNA repair pathways, and
pathways invol ved in xenobiotic metabolism. All of these pathways in one-way or
the other play a role in the modulation of infection by HPV and hence the suscepti-
bility to cervical cancer.
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7.2.1 HPV Pathogenesis
The infection by human papilloma virus, the main cause of cervical cancer, serves as
the founder effect for cancerous transformation of cells (Chen et al. 2011). Human
papilloma viruses belong to Papovaviridae family of DNA viruses and are
Table 7.2 FIGO Staging of cervix uteri carcinoma (2018) (cancer confined to cervix uteri.
Invasion into corpus not considered)
Stage Description
I
IA Cancer is invasive with a maximum depth <5 mm, diagnosis possible by microscopy
only
a
IA1 Invasion into stroma with a maximum depth <3mm
IA2 Invasion into stroma with a maximum depth 3 mm and <5mm
IB Cancer is invasive with a maximum depth 5 mm but lesion is confined to cervix uteri
b
IB1 Invasion into stroma with a maximum depth 5 mm and greatest dimension <2cm
IB2 Cancer invasion with greatest dimension 2 cm and <4cm
IB3 Cancer invasion with greatest dimension 4cm
II Cancer invasion beyond uterus but has not reached the lower third of vagina or the wall
of pelvis
IIA Cancer invasion into upper two-thirds of vagina but parametrium is not involved
IIA1 Cancer invasion with greatest dimension <4cm
IIA2 Cancer invasion with greatest dimension 4cm
IIB Cancer invasion into parametrium but the wall of pelvis is not involved
III Cancer invasion into lower third of vagina and/or the wall of pelvis. Paraaortic/pelvic
lymph nodes involved. May be associated with hydronephrosis and renal failure
c
IIIA Cancer invasion into the lower third of vagina but the wall of pelvis is not involved
IIIB Cancer invasion into the wall of pelvis. May be associated with hydronephrosis and renal
failure
IIIC Cancer invasion into pelvis. Pelvic/paraaortic lymph nodes involved. Involvement does
not depend on size and extent of tumor (r and p notations)
c
IIIC1 Cancer metastasis into pelvic lymph nodes only
IIIC2 Cancer metastasis into paraaortic lymph nodes
IV Cancer invasion beyond true pelvis. Bladder and/or rectal mucosa involved (proven
through biopsy examination). Mere presence of bullous edema not sufficient for stage IV
diagnosis
IVA Cancer invasion and metastasis into adjacent organs
IVB Cancer invasion and metastasis into distant organs
a
To assess the size and extent of tumor, in addition to clinical findings, imaging and histopath-
ological diagnosis should be used wherever possible
b
Lymph/vascular involvement and lateral extension of tumor are not considered for change of stage.
c
For using r (imaging) and p (pathology) notations to denote finding in order to allocate stage IIIC,
the following points should be considered:
If imaging reveals metastasis of lymph nodes of pelvis, allocate stage IIIC1r
If metastasis of lymph nodes of pelvis is confirmed through pathological examination, allocate stage
IIIC1p
The imaging and pathological techniques used should be clearly indicated through proper docu-
mentation. In case there is still some degree of doubt, allocate lower stage
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epitheliotropic, known to infect mucosa and skin. Out of about 200 HPV types, a
minimum of 40 HPV types have been demonstrated to cause infection of the
mucosal lining of anogenital tract (Chan et al. 2019; Zur Hausen 2002). Around
15 HPVs identified to have a high capacity to lead to the malignant transformation
are referred to as high risk HPVs (HR-HPV). In almost 70% of all the cases of CC,
the infection by HR-HPV types, which are highly virulent, in particular, HR-HPV
type 16 and HR-HPV type 18, has been detected. Further, HR-HPV type 16 has been
associated with 24% of all HPV infections in women whereas HR-HPV type 18 has
been associated with 9% of all HPV infections in women (Chan et al. 2019; Tulay
and Serakinci 2016; Crosbie et al. 2013; Burd 2003).
The genome of papillomavirus consists of a single highly conserved double-
stranded DNA (ds-DNA), about 8 kilo base pairs (kbp) in size. The HPV DNA
contains three essential regions—an early (E) region, a late (L) region, and a long
control region (LCR). The early region makes up about 4 kbp, the late region makes
up about 3 kbp, and the LCR makes up the rest of the HPV genome (Chan et al.
2019; Crosbie et al. 2013; Hemmar and Bannazadeh 2019). Figure 7.2 gives a
graphical representation of HPV-16 genome. The early (E) region of HPV genome
consists of six genes, namely, E1, E2, E4, E5, E6, and E7, which as the name implies
are transcribed and translated foremost in the life cycle of HPV. The early region
genes are expressed immediately once the HPV makes its entry into the host cell.
The late region genes are encoded into proteins, which are needed in later stages of
HPV cycle. These proteins are critical for the lytic phase of the HPV life cycle. The
long control region performs regulatory function and with the help of its various cis
E6
E7
E1
E4
E2
E5
L2
L1
HPV-16
Early Genes
Late Genes
Long Control Region
LCR
Fig. 7.2 The HPV-16 genome. The various regions of HPV genome and the proteins it encodes are
shown in different colors. The orange arrow represents the origin of replication
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containing elements, it regulates the replication and expression of HPV genome
(Chan et al. 2019; Tan and Ankathil 2015). Table 7.3 enlists the various HPV
proteins and their related functions.
The HPV genome encodes eight different proteins, six early proteins designated
as E1, E2, E4, E5, E6, and E7 and two late proteins designated as L1 and L2. Of the
six early proteins, three proteins E1, E2, E4 serve as regulatory proteins whereas the
other three proteins E5, E6, and E7 are oncoproteins. Two late proteins, L1 and L2
are the structural ones, which make up the capsid of virus (Chan et al. 2019; Hemmar
and Bannazadeh 2019).
E5 protein of HPV plays a pivotal role in the early course of infection. The
oncoproteins, E6 and E7 immortalize the infected human cells through interactions
with numerous gatekeeper proteins like p53, RB, INK4A, cyclin D and E, which
ultimately leads to dysregulation of several important pathways involved in DNA
repair and cell cycle regulation (Narisawa-Saito and Kiyono 2007; Zur Hausen
2002). After the initial infection, HPV early region genes, E6 and E7 are retained
within the host cell and subsequently integrated into the genome of the host cell for
their constant and continuous expression (Chan et al. 2019).
HR-HPV E6 protein is composed of about 150 amino acid residues and it
interacts with numerous proteins in the host cell through its PDZ-binding motifs
and zinc finger domains. E6 mainly binds tumor suppressor, p53; for this binding
another protein, E6-associated binding protein (E6AP) is crucial, and these proteins
form E6/E6AP/p53 trimeric complex. Generally, HR-HPV E6 has been shown to
interfere primarily with the degradation of p53, its main target. However, it also
interferes with telomerase activation, genome stability, regulation of microRNAs,
and G protein signaling. It leads to immortalization of infected host cell and causes
disruption of innate immune system, dysregulation of cellular apoptotic signaling,
and changes in cell adhesion, cell polarity, and cellular differentiation (Chan et al.
Table 7.3 List of HPV proteins and their function
HPV
Protein Functions
E1 It is known to initiate DNA replication in viral genome, acts as repressor of host
transcription and replication
E2 It functions in concomitance with E1 and activates coding of proteins known to
regulate viral DNA transcription, cellular transformation, modulating apoptosis,
and regulating the HPV transformation towards higher CIN stages by regulating E6
and E7 transcription and expression
E4 It helps in the formation of nodules in the host cell and hence in regulating the cell
cycle
E5 It is pivotal during the early course of infection by influencing the viral DNA
transformation and initiating early DNA replication
E6 It helps in maintaining the viral DNA replication together with E5 and also
interferes with the degradation of p53 affecting apoptosis and promotes the
transformation of cell into malignant ones
E7 It mainly binds retinoblastoma protein (pRb) which results in the malignant
transformation
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2019; Crosbie et al. 2013; Hemmar and Bannazadeh 2019). Figure 7.3 summarizes
the role played by HR-HPV E6/E7 in the carcinogenesis of cervical cancer.
HR-HPV E7 protein is composed of about 100 amino acid residues. E7 mainly
binds retinoblastoma protein (pRb), another important tumor suppressor and leads to
its inactivation and degradation. The binding of E7 to pRb results in the disruption of
interaction between pRB and its downstream target E2F, a transcription factor,
which is consequently upregulated causing failure of the maintenance of S-phase,
HPV episome
integration
HPV Early gene
expression
E6
Degradation of p53 (E6/E6AP/p53)
Inactivation & Degradation of pRb
Stabilization of Telomerase
Prevents senescence
Binds to PDZ domain proteins
Degradation of secondary tumor
suppressors – Dlg, Scribble
Activates mTOR & WNT pathways
Epigenetic silencing via
Sustained
Expression
• Increased hypermethylation
• Uncontrolled proliferation
• Binding to HATs
• Deregulation of miRs
• DNMTs binding
• Apoptosis dysregulation
• Proliferation
• Evasion of suppression
• Invasion and Metastasis
• Angiogenesis
• Failure of Apoptosis
• Replicative immortality
• Cell cycle failure
• AKT pathways activation
Transformed
Host Cell
GENETIC INSTABILITY
E6/E7 combined effect:
Leading to hallmarks of cancer:
E7
Normal Host
Cell
Fig. 7.3 Progression of cervical carcinogenesis. The transformation of the host cells encompasses
the integration of the HPV genetic material into the genetic material of host, leading to continuous
expression of two important early genes E6 and E7 which in turn trigger a host of dysregulations in
the various pathways via inhibiting the function and leading to degradation of p53 and pRB,
eventually leading to carcinogenesis
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and hence cellular proliferation (Chan et al. 2019; Crosbie et al. 2013; Hemmar and
Bannazadeh 2019). HR-HPV E5, E6 and E7 proteins are also known to regulate the
expression of various micro RNAs (miRs) which are involved in carcinogenesis and
most of which are reported to be overexpressed (miR-375, miR-143, miR-21,
miR-9) (Chan et al. 2019; Jung et al. 2014; Groves and Coleman 2015). Further-
more, E6 and E7 have also been reported to affect the functionality of DNA methyl
transferases (DNMTs) leading to hypermethylation of critical CpG islands of many
tumor suppressor genes of the host genome, thereby paving the way for initiation
and proliferation via failure of DNA repair mechanisms (Burgers et al. 2007).
7.3 Polymorphisms and Cervical Cancer
The modulation of susceptibility of CC by the genetic variants especially polymor-
phism is of utmost importance in understanding the interaction between the HPV
infection and polymorphic status of various genes. In this chapter we would be
discussing the effects of polymorphisms of specific genes involved in various critical
pathways like immune response, apoptosis control, antigen processing, DNA repair,
and xenobiotic metabolism in modulating the risk of cervical cancer.
7.3.1 Polymorphisms in Immune Response Genes
Although the exact molecular mechanisms and hence the genes involved in the
initiation and progression of CC as a result of the chronic HPV infection are not
known, it has been postulated that both innate immunity and adaptive immunity of
the host do play a pivotal role in the regression, persistence, and/or development of
HPV infection. All these result in the transformation of the cervical walls to undergo
transformation into the cancerous tissue (Chen et al. 2011). In immune response
mechanisms, numerous proteins and hence their genes are involved: tumor necrosis
factor-α (TNF-α), interferon-γ (IFNG), cytotoxic T-lymphocyte antigen-4 (CTLA-
4), human leukocyte antigen (HLA), and many cytokines including interleukins
(IL-1β, IL-12β, IL-10).
7.3.1.1 TNF-a
Tumor necrosis factor alpha (TNF-α) is a vital proinflammatory, pleiotropic cytokine
expressed by activated macrophages and by several cells including lymphocytes,
neutrophils, eosinophils, and neurons (Schwabe and Brenner 2006). TNF-α is one of
the members of tumor necrosis factor (TNF) superfamily which comprises 19 ligands
and 29 receptors all of which perform diversified roles in the body. TNF-α is a
central molecule in various vital cellular processes including inflammation, immu-
nity, cell growth, proliferation, apoptosis, cellular differentiation, and organization
(Aggarwal et al. 2012; Balkwill 2006, 2009). Out of the diverse roles which TNF-α
plays, some of the important ones are: viral infections defense, mediation in the
inflammatory and acute-phase responses, performing immune-regulatory activities
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by activating other cytokines and adhesion functions using endothelial adhesion
molecules (Aggarwal et al. 2012; Balkwill 2006, 2009).
TNF-α gene is present in short arm of chromosome 6 (p21.33). It primarily
encodes a 26 kDa membrane-bound protein which in turn produces terminal
17 kDa active TNF-α protein via a proteolytic cleavage by metalloproteinase—
disintegrin (TNF-α converting enzyme—TACE) (Raabe et al. 1998). TNF-α gene
expression is tightly regulated at transcriptional level by multiple potential regu-
latory sites located in the 5
0
-flanking regions of the gene (Aggarwal et al. 2012;
Raabe et al. 1998). This region is also home to polymorphic sites which coincide
with the DNA motifs to which transcription factors like activator protein-1 and
2 (AP-1 and AP-2) bind, thereby regulating the expression (Liu et al. 2012). In the
promoter region of TNF-α gene, two critical SNPs have been reported, both of which
are known to affect its transcription. One is the G to A transition (G308A,
rs1800629) at 308 bp position and the other less common is the G to A transition
at 238 bp position (G238A, rs361525) within the promoter hotspot regulatory
region of the gene (Liu et al. 2012; Pan et al. 2012). Both are known to affect the
TNF-α production, e.g., TNF-α-308A allele is reported to be associated with higher
constitutive and inducible expression of TNF-α in comparison with TNF-α-308G
allele (Abraham and Kroeger 1999).
Both SNPs of TNF-α gene have been extensively reported upon for their modu-
lation of CC risk (Du et al. 2019; Ding et al. 2012; Liu et al. 2012; Pan et al. 2012).
Pan et al. (2012) in their meta-analysis reported that TNF-α-238A allele significantly
decreased the risk of CC [OR ¼ 0.61, 95% CI ¼ 0.47–0.78] while TNF-α-308G > A
SNP was significantly associated with the susceptibility to CC in Caucasian and
African population [OR ¼ 1.43, 95% CI ¼ 1.00–2.03; OR ¼ 1.53, 95%
CI ¼ 1.02–2.30, respectively]. Similarly, Liu et al. (2012) also reported a significant
association of variant homozygous genotype –308AA with an increased CC risk
[OR ¼ 1.41, 95% CI ¼ 1.03–1.92] with the effect being more reflective in Asian
population [OR ¼ 3.67, 95% CI ¼ 1.25–10.81].
Thus, these results suggest that TNF SNPs may serve as the important suscepti-
bility factors for cervical cancer tumorigenesis. And hence can be used as
biomarkers for the disease. Another meta-analysis also reported TNF-α-308G > A
SNP to be associated with the increased risk of cervical lesions [OR 1.22, 95%CI
1.04–1.44], especially in Caucasians but not in Asians [OR 1.24, 95%CI 1.05–1.47]
(Li et al. 2013). In recent meta-analysis by Wang et al. 202 0 , it was reported that both
TNF-α -G238A and -G308A SNPs could be used as the biomarkers for identification
of individuals with elevated susceptibility in both Asian and Caucasian populations.
Besides these two SNPs, there are other two SNPs which are less evaluated but do
play role in cancer susceptibility which are TNF-α T-857C (rs1799724) and TNF-α
T-1031C (rs1799964) (Wang et al. 2016).
7.3.1.2 IFN-g
Interferon Gamma (IFN-γ) like TNF is an important multi-functional cytokine
secreted by cytotoxic T cells, CD4
+
type-1 helper (Th1) T cells, and activated natural
killer (NK) cells. IFN-γ is usually produced in respon se to the stimulation by foreign
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antigens which in turn plays a role in activating macrophages and endothelial cells
(Woodman et al. 1991). Apart from IFN-γ, the two other important interferons are
IFN-α, IFN-β, IFN-ω, and IFN-τ. IFNs are known to enhance the immune response
by activating and promoting the functions of T- and NK-cells. It usually promotes
the antigen presentation via antigen-pr esenting cells (APCs) by enhancing antigen
recognition, increases the reactive oxygen species (ROS) production, and induces
antiviral responses (Kak et al. 2018). The production of IFN-γ is tightly regulated
by various APCs through secretion of various cytokines, most importantly inter-
leukins: IL-12 and IL-18, which act as a link between the HPV infection and IFN-γ
production in innate immune response (Schroder et al. 2004).
IFN-γ is translated from IFN-γ gene, a 5.4 kb long sequence, present on the long
arm of chromosome 12 (12q24). IFN-γ gene consists of four exons with three
intervening regions (Stark et al. 1998) and has been reported to contain as much as
seven different genetic variations including one microsatellite CA repeat and six
SNPs [Fig. 7.4]. The SNP +874 of IFN-γ (+T874A, rs2430561), located in the
intronic region between exon 1 and exon 2 is the most studied of all, which results
due to substitution of T with A (Sun et al. 2015a, b). This SNP has been reported to
affect the IFN production, with TT genotype related to high IFN expression, in
response to the stimuli (Schena et al. 2006).
Because of the role played by IFN-γ in antiviral immunity, several studies have
reported on the effect of IFN-γ + T874A (rs2430561)SNP in predisposing
individuals to cervical cancer in the context of persistent high-risk HPV infection
(Mehta et al. 2017a, b; Liu et al. 2015; Sun et al. 2015a, b; Maskoen et al. 2013;
Wang et al. 2011; Kim et al. 2003). Sun et al. (2015a, b) in their meta-analysis
reported that in the codominant model, IFN-γ + T874A SNP signi ficantly increased
the risk of CC [OR ¼ 1.471, 95%CI ¼ 1.137–1.903], and there was an increased risk
of cancer in Asian individuals as well [OR ¼ 1.494, 95% CI ¼ 1.069–2.087].
Similarly, Liu et al. (2015) also reported an increased risk of CC in Asian individuals
[OR
¼ 1.11, 95% CI ¼ 0.61 ~ 2.02].
7.3.1.3 CTLA-4
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is another important inhibitory mole-
cule which has a critical role in immune system functioning. It is particularly
involved in the downregulation of T-cell activation and peripheral tolerance (Wing
et al. 2011). CTLA 4 is a gene located on human chromosome 2q33. In humans,
CTLA-4 exists in two splice variants as a result of alternative splicing—one is
membrane-bound CTLA-4 possessing 4 exons: exon 1 encodes a leader peptide,
exon 2 encodes ligand binding domain, exon 3 encodes transmembrane domain, and
exon 4 encodes cytoplasmic domain. The splice variant of CTLA-4 does not have
exon 3 and hence it lacks the transmembrane spanning domain resulting in the
expression of the soluble CTLA4 (sCTLA-4) (Wagh et al. 2018; Pawlak et al. 2005).
Several p olymorphisms of CTLA-4 gene have been reported to increase the
susceptibility of various auto immune and malignant diseases (Fernández-Mestre
et al. 2009; Johnson et al. 2001). In CTLA-4 gene locus about 16 SNPs and an (AT)n
microsatellite have been reported, however, only three of them (SNP +49, 318, and
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Fig. 7.4 Schematic diagram showing the position of different SNPs present within the IFN-γ gene on chromosome 12q24
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