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This model first proposed by Bert Vogelstein in 1988 describes the accumulation
of mutations in various signaling pathway genes that are involved in regulation of
cell survival, cell proliferation, cell differentiation, and apoptosis. The mutations in
these various specific genes result in dysregulation of these critical cellular processes
and ultimately lead to colorectal cancer (Fearon and Vogelstein 1990; Fearon 2011).
In rest of the CRC cases (5–10%), the tumorigenic transformation of epithelium into
adenocarcinomas occurs through an alternative, well-characterized, and sequential
multi-step process, which also involves specific genetic and histological changes,
and is known as serrated neoplastic sequence of colorectal carcinogenesis or the
serrated pathway.
The genomic instability is the underlying cause of colorectal cancer (sporadic and
inherited). It occurs mainly through three main pathways, which although distinct
with regard to molecular characteristics often show a considerable intersection in
colorectal tumorigenesis. The three pathways responsible for genomic instability in
colorectal tumorigenesis include chromosomal instability (CIN) pathway, microsat-
ellite instability (MSI) pathway, and CpG island methylator phenotype (CIMP)
pathway (Armaghany et al. 2012).
Box 5.1 Adenoma-Carcinoma Sequence (Vogelstein Model)—Main
Features
• Colorectal cancer arises from gain of function mutations in proto-
oncogenes and loss of function mutations in tumor suppressor genes.
• Transformation of normal cell into malignant form requires accumulation
of somatic gene mutations, or in other words, malignant transformation
requires somatic mutations in multiple genes; a minimum of four to five
genes.
• The fate of tumorigenesis or tumor characteristics is determined by the
nature of accumulated mutations in the multiple genes involved and not by
the sequence of these mutations.
• The sequential multi-step process observed in colorectal tumorigenesis is
not exclusive to CRC but stands valid for other solid tissue tumors includ-
ing that of pancreas, breast and stomach.
5.2.1 Chromosomal Instability (CIN) Pathway
Genomic instability in colorectal tumorigenesis mainly occurs through chromosomal
instability (CIN) pathway (suppressor pathway), which represents the underlying
cause of 80–85% of all the cases of colorectal cancer (Goel et al. 2003; Grady 2004).
CIN pathway is characterized by dynamic and continuing changes in chromosome
structure, chromosome number, and gene mutations, which affects the normal
functioning of important genes, involved in critical cellular processes and leads to
the development of colorectal tumors. The changes in chromosome structure occur
due to loss of chromosomal regions (sub-chromosomal deletions) or gain of
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chromosomal regions (sub-chromosomal amplifications) and changes in chromo-
some number occur due to loss or gain of whole chromosomes.
The gain of function mutations in proto-oncogenes and loss of function mutations
in tumor suppressor genes, often referred to as cell ular gatekeeper genes, most often
initiate the CIN pathway (McGranahan et al. 2012). The mutations in gatekeeper and
several other important genes cause dysregulation or dysfunction of a number of
signaling pathways , which promotes various cellular processes or events that
describe CIN pathway. The prominent among these events include defects in
chromosomal segregation, atypical centromere number; defects in centromere func-
tion, telomere function and DNA damage response and include loss of heterozygos-
ity (LOH) (Pino and Chung 2010). Defects in chromosomal segregation, which
results in aneuploidy (abnormal chromosomal number), occur mostly due to the
mutations in genes, which regulate mitotic checkpoint or spindle assembly check-
point (Boveri 2008). Defects in centromere number and function cause uneven
distribution of chromosomes (Ganem et al. 2009). Telomere dysfunction as an
initiating event for CIN pathway involves telomere shortening but subsequently
involves increased telomerase expression, a CIN pathway independent event, which
promotes tumor proliferation and survival (Plentz et al. 2003). Loss of heterozygos-
ity (LOH), characterized by the loss of one allele at a certain chromosomal location is
an important initiating event in colorectal tumorigenesis involving CIN pathway.
LOH results from various molecular or chromosomal events including chromosomal
deletions, mitotic non-disjunction and recombination between homologous
chromosomes (Thiagalingam et al. 200 1 ). LOH with a varied freque ncy has been
reported across different chromosomal loci throughout the genome in most cases of
sporadic colorectal cancer. LOH involving chromosomal loci, which carry tumor
suppressor genes, is among the most frequent and critical events in colorectal
tumorigenesis (Pino and Chung 2010).
Loss of chromosomal regions (sub-chromosomal deletions) have been reported in
certain regions on chromosomes 1, 4, 5, 8p, 14q, 15q, 17p, 18, 20p, and 22q and gain
of chromosomal regions (sub-chromosomal amplifications) have been observed in
case of chromosomes 7, 8q, 13q, 20, and X. The sub-chromosomal deletions and
sub-chromosomal amplifications have been reported to affect various genes includ-
ing MYC, VEGF, MET, PTEN, LYN, and these genes are known to play critical
roles in colorectal tumorigenesis. Loss of whole chromosome as a CIN pathway
event has been most frequently reported for chromosome 18 (Thiagalingam et al.
2001).
Defects in chromosomal segregation arise due to mutations in genes involved in
function and regulation of mitotic checkpoint including budding uninhibited by
benzimidazoles 1 (BUB1), mitotic arrest deficient like (MAD1L1 and MAD2L1),
kinesin spindle protein (Eg5) and kinesin family member 11 (KIF11) (Castillo et al.
2007). Various genes involved in regulation of cell cycle regulation including cyclin
D1 gene (CCDN1), cyclin E gene (CCNE1), retinoblastoma gene (RB1), and `c-myc
gene (MYC) when deregulated may cause chromosomal instability (CIN) (Lung
et al. 2002; Spruck et al. 1999; Hernando et al. 2004; Vafa et al. 2002). Defects in
centromere number and function arise due to deregulation of genes, which include
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genes coding for centrosome-associated Aurora A kinase (AURKA) and Polo-like
kinases (Plk) (Dotan et al. 2012). Loss of heterozygosity (LOH) mostly involves
chromosomes 1, 5, 8, 17, and 18 and the highest frequency ranges (46–78%) have
been reported across different loci on these chromosomes. LOH involving chromo-
somal loci, which carry tumor suppressor genes, includes 5q21 (APC gene), 9p (p16
and p15 genes), 13q (Rb gene), 3p21 (beta-catenin gene), 17p (p53 gene), 17q
(BRCA1 gene), 18q (Deleted in Colorectal Cancer/DCC, SMAD2 and SMAD4
genes), and 16q (E-cadherin gene) but with less frequency (Thiagalingam et al.
2001; Conlin et al. 2005). Mutations in genes, APC, and KRAS have been frequently
associated with chromosomal instability (CIN) pathway (McGranahan et al. 2012).
5.2.2 Microsatellite Instability (MSI) Pathway
Microsatellites (MSs), also known as simple sequence repeats (SSRs), are regions of
DNA which contain short sequence repeats with each repeat one to six (usually two
to four) nucleotides in length. Microsatellites exhibit high variability in length and
the short sequences, which constitute MSs, are repeated usual ly five to fifty times.
MSs are dispersed across the whole genome and occur in coding regions (exons) as
well as non-coding regions (promoters, introns, and untranslated regions/UTR s) of
the genome.
Microsatellites are highly susceptible to errors during DNA replication mostly in
the form of insertion or deletion mutations (insertion-deletion loop). The insertion-
deletion loop alters the length of MSs and leads to microsatellite instability (MSI).
However, DNA mismatch repair (MMR) system, which consists of genes that code
for various proteins including MLH1, MLH3, PMS1, PMS2, MSH2, MSH3, MSH6,
and EXO1, plays a critical role in maintenance of microsatellite stability through
recognition and correction of errors introduced during DNA replication. The
improper functioning of mismatch repair system due to defect in any of the genes
or prote ins involved results in frame-shift mutations. The buildup of these mutations
in the genome, and in particular, in the genes, which contain microsatellites leads to
microsatellite instability (MSI). MSI is an important molecular event responsible for
colorectal tumorigenesis. Microsatellite instability (MSI) pathway (mutator path-
way) is another important contributor towards genomic instability in colorectal
tumorigenesis after CIN pathway and represents the underlying cause of 15–20%
of all the cases of colorectal cancer (Boland and Goel 2010).
MSI pathway is the most important event in tumorigenesis of hereditary
non-polyposis colorectal cancer (HNPCC), which results in dysfunction and
dysregulation of MMR system due to heritable (germline) mutations in MMR
genes (de la Chapelle and Hampel 2010). MSI plays a major role in the pathogenesis
of about 21% of premalignant (dysplastic) lesions and 19% of malignant tumors in
ulcerative colitis (UC). MMR dysfunction and dysregulation due to somatic
mutations in MMR genes or MMR gene silencing by hypermethylation also lead
to colorectal cancer associated MSI and present with specific pathological and
phenotypic characteristics. MSI associated colorectal tumors are mostly poorly
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differentiated tumors, which arise on the right side of the colon, proximal to splenic
flexure. These tumors mostly affect older women and exhibit atypical histology with
an increased infiltration by lymphocytes in the peri-tumoral and intratumoral regions
as seen in Crohn’s disease (Benatti et al. 2005; Iacopetta et al. 2010).
Genomic instability in colorectal tumorigenesis resulting from MSI has been
reported in several genes or gene classes, which are involved in vital cellular
processes including cell cycle regulation (RIZ and PTEN), apoptosis (BAX,
APAF1, BCL-10, and caspase 5), and DNA repair (MLH1, MLH3, MSH2,
MSH3, MSH6, RAD50, PMS2, MBD4, and BLM). Colorectal cancer associated
MSI has also been reported in several important signal transduction molecules
including APC, β-catenin, transforming growth factor β type II receptor (TGFβRII),
activin type II receptor (ACTRII), insulin-like growth factor-II receptor (IGFIIR),
and transcription factors including E2F4 and TCF-4 (Iacopetta et al. 2010; Soreide
et al. 2006).
5.2.3 CpG Island Methylator Phenotype (CIMP) Pathway
DNA methylation is a critical epigenetic mechanism for regulation of gene expres-
sion. DNA methylation involves the enzymatic addition of methyl group to cytosine
base and most frequently occurs at sites where a cytosine (C) is followed by a
guanine (G), represented as dinucleotide CpG (5’-C-phosphate-G-3
0
) or simply
CG. Although not present frequently throughout the genome, CpG dinucleotides
are often found clustered together in regions known as CpG islands. The CpG
islands are most frequently found in gene promoter regions, upstream and proximal
to the transcription start site in about 70% of all the human genes (Deaton and Bird
2011). The methylation of gene promoter CpG islands suppresses or inhibits gene
transcription by directly affecting the binding of transcription factors and through
modulation of histone modifications, in particular, acetylation. Both these processes
lead to gene silencing. DNA methylation and the gene silencing it induces are tightly
regulated cellular processes essential for normal cellular function but under
deregulated conditions, there is increased DNA methylation or hypermethylation
which induces aberrant gene silencing and may lead to various diseases including
cancer (Wong et al. 2010 ).
CpG island methylator phenotype (CIMP) pathway (novel mutator pathway)
results mainly from increased DNA methylation or hypermethylation of CpG
islands, which leads to silencing of important genes or gene classes. These include
cell cycle regulatory genes [Mutated in Colorectal Cancers (MCC)], tumor suppres-
sor genes [Adenomatous polyposis coli (APC), p16, insulin-like growth factor
2 (IGF-2), and hypermethylated-in-cancer 1 (HIC-1)], DNA repair genes [MLH1
and methylguanine methyltransferase (MGMT)] and Wnt signaling antagonists, the
secreted frizzled-related proteins (SFRPs) (Kim et al. 2010; Goel et al. 2007). CIMP
pathway represents the underlying cause of 15% to 20% of all the cases of sporadic
colorectal cancer (Weisenberger et al. 2006).
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Although CI N pathway, MSI pathway, and CIMP pathway can independently
lead to colorectal cancer, either two or all the three pathways can operate together
and lead to initiation and progression of colorectal cancer (Fearon 2011; Hanahan
and Weinberg 2011).
5.3 Polymorphisms and Colorectal Cancer
The genetic variations or variations in DNA between different individuals or
populations are widespread across the human genome and constitute about
0.1–0.4% of the whole genome. The genetic variations exist in different forms or
types, and the most common forms include single nucleotide polymorphisms
(SNPs), insertions or deletions (indels), and copy number variations (CNVs).
SNPs, which involve substitution of single nucleotide, are of two types, transition
and transversion. Transition involves substitution of one purine (adenine or guanine)
by another purine (guanine or adenine) or substitution of one pyrimidine (cytosine or
thymine) by another pyrimidine (thymine or cytosine) whereas transversion involves
substitution of purines by pyrimidines and vice versa. Insertion or deletion (indel)
involves insertion or deletion of nucleotides ranging from one to hundreds of
nucleotides. Copy number variation, a structural variation, involves variation in
number of times a particular stretch of DNA is repeated across the human genome
(Karki et al. 2015; Savas and Liu 2009). As already discussed in introductory
chapter, genetic variations across entire genome mostly exist as SNPs. An estimated
more than 10 million SNPs are spread across the entire human genome (Karki et al.
2015; Sudmant et al. 2015).
SNPs can directly or indirectly alter gene regulation and function and modulate
susceptibility to various diseases including cancers such as CRC. Several different
types of studies involving different populations across the world have reported the
association and role of SNPs in modulating the susceptibility to various diseases.
Several SNPs have been identified as potential biomarkers for CRC as well (Law
et al. 2019; Xin et al. 2019; Huyghe et al. 2019; Alegria-Lertxundi et al. 2019; Wen
et al. 2018; Tan 2018; Wang et al. 2017a).
The role played by the genetic variants especially SNPs in modulating the risk of
CRC is of very diverse nature. In this chapter, we would be discussing the effects of
SNPs in the low penetrance genes depending upon the type of pathways these genes
are involved in. Numerous pathways, which are known to get affected by genetic
variations, can be categorized as: cell cycle regulatory, transcription regulatory,
DNA repair, folate metabolism, fat metabolism, xenobiotic and inflammatory
pathways. A detailed description of inflammatory pathway genes and their
polymorphisms in gastric cancer is given in Chap. 7. In this chapter, we will be
discussing the importance of various pathways mentioned earlier and the
polymorphisms, which have been reported in different genes of these pathways to
be associated with colorectal cancer.
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5.3.1 Polymorphisms in Cell Cycle Regulatory Genes
Cancer is a clonal disorder, which is primarily characterized by a dysregulation of
cell growth, division, and differentiation (Hanahan and Weinberg 2011). The genetic
polymorphisms, which affect the genes responsible for maintaining the control of
such events, have a potential to disrupt the growth and differentiation of the normal
cells diverting them to the path of carcinogenesis. Thus, polymorphisms in genes,
which are involved in regulation of cell growth and division, are the focus areas for
the geneticists to understand their role in colorectal carcinogenesis.
5.3.1.1 APC Gene Polymorphisms
Adenomatous polyposis coli (APC) gene is one of the most important genes, which
in dysregulated form is an important mediator of colorectal cancer initiation and
early progression via CIN pathway (Fearon and Vogelstein 1990). APC gene
(chromosomal location, 5q21-q22) consists of 21 exons, encoding a transcript
9.0 kilobase (kb) in size, which translates into APC protein containing 2843 amino
acids (Sameer et al. 2011). APC protein functions as a classical tumor suppressor
primarily by regulating the intracellular β-catenin oncoprotein (Aoki and Taketo
2007; Kennell and Cadigan 2009). Loss of function mutations in APC gene results in
the accumulation of β-catenin, which causes atypical cellular proliferation and has
been reported to be involved in the pathogenesis of approximately 60–80% of
sporadic carcinomas and adenomas. Germ-line mutations in APC gene are the
hallmarks of the inherited (Hereditary) CRC and familial adenomatous polyposis
(FAP) (Zhan et al. 2017; Fodde et al. 2001).
Several putative SNPs have been reported in APC gene, which affect its func-
tioning (Liang et al. 2013; Wong et al. 2010; Walther et al. 2009; Tranah et al. 2005).
Out of the eight interrogated SNPs, present in the APC gene of which some affect the
intronic region and some affect the exons. Four exonic germline SNP variants have
been extensively studied in many populations across the world which are APC
I1307K (rs1801155), E1317Q (rs1801166), D1822V (rs459552), and G2502S
(rs2229995) (Wong et al. 2010), because these SNPs are non-synonymous which
lead to substitution of amino acids. The resulting amino acid change affects the
β-catenin binding region of APC protein and hence changes the functionality of APC
mediated regulation (Zhan et al. 2017; Fodde et al. 2001).
Various association studies have shown that APC gene SNPs modulate the risk of
colorectal carcinoma. Liang et al. (2013) in their HuGE review and meta-analysis
study concluded that APC I1307K SNP is significantly associated with CRC risk
among Ashkenazi Jews [odds ratio (OR), 2.17, 95% confidence interval (Cl),
1.64–2.86); p < 0.01]. Wong et al. (2010) reported that APC D1822V SNP is
significantly associated with risk of advanced distal adenom a among individuals
consuming high fat diet [(OR, 0.74, 95%CI, 0.5–1.0); p < 0.03]. Similarly, Walther
et al. (2009) reported a significant association between APC E1317Q SNP and
colorectal adenoma [(OR, 2.89, 95% CI, 1.83–4.56); p < 0.01]. However, Tranah
et al. (2005) had reported that APC Asp1822Val and Gly2502Ser SNPs had no
association with risk of either CRC or adenoma in both men and women.
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5.3.1.2 CCDN1 Gene Polymorphisms
CCND1 gene encodes Cyclin D1 (CCND1) protein, which is an important member
of cyclin protein family, which regulates the function and activity of cyclin-
dependent kinases (CDKs). CDKs (CDK4 and CDK6) play a vital role in G1 to S
phase transition of cell cycle. Cyclin D1 regulates the activity of CDKs by forming a
complex with them. Cyclin D1 as a regulatory component of cyclin D1-CDK4
complex phosphorylates retinoblastoma (RB) protein family members including
RB1 and inhibits their activity. The phosphorylation of RB1 results in the release
of transcription factor E2F from RB-E2F complex, which in turn transactivates
various target genes involved in G1 to S phase transition of cell cycle (Sherr and
Roberts 2004).
Cyclin D1 gene (chromosomal location, 11q13) encodes Cyclin D1 (CCDN1)
protein containing 295 amino acids (Knudsen et al. 2006). The overexpression of
Cyclin D1 protein has been reported in various types of cancers including colorectal
cancer, where its abnormal expression is reported in around 55–62% of all CRC
cases. The overexpression of Cyclin D1 protein leads to aberrant cell cycle control at
G1 to S phase transition and promotes abnormal cell growth and division character-
istic of cancer (Balcerczak et al. 2005).
One of the most common polymorphisms that has been extensively studied in
CCDN1 gene is the splice donor region G to A SNP of exon 4, located at codon
242 of the gene (G870A, rs9344). This SNP affects CCDN1 gene splicing and G to
A transition of this SNP results in the preferential production of short transcript b,
which encodes the CCDN1 protein isoform possessing a longer half-life (Kong et al.
2001). A number of meta-analyses studies have shown that there is a significant
association between CCDN1 G870A SNP and risk of colorectal cancer. The allele A
of G870A SNP showed a significant association with an increased risk of CRC in
both Asian and Caucasian populations [OR Range ¼ 1.09–1.28] (Xie et al. 2017;
Qui et al. 2016; Xu et al. 2016; Yang et al. 2012).
5.3.1.3 CHEK2 Gene Polymorphisms
CHEK2 gene (chromosomal location, 22q12.1) encodes cell cycle checkpoint kinase
2, a serine/threonine kinase involved in regulation of vital cellular processes includ-
ing cell cycle progression, more specifically G2 to M phase transition, DNA damage
repair involved in preservation of genome integrity, and apoptosis (Bartek and Lukas
2003). Checkpoint kinase 2 causes cell cycle arrest and promotes activation of DNA
damage repair and apoptosis in response to presence of DNA damage, especially
DNA double-strand breaks (DSBs) (Stolz et al. 2011). Under normal cellular
conditions, CHEK2 protein exists in an inactive form. It is activated in response to
presence of DNA damage, especially DSBs. The activation occurs through phos-
phorylation, catalyzed by ataxia telangiectasia mutated (ATM) serine/threonine
kinase. The activated CHEK2 protein in turn phosphorylates many downstream
protein targets including TP53 and CDC25 to mediate control over cell cycle
progression (Bartek and Lukas 2003).
One of the most common polymorphisms that has been extensively studied in
CHEK2 gene is T470C (I157T, rs17879961) SNP, which affects the codon 157 and
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leads to the production of missense variant in which isoleucine residue is replaced by
threonine in the forkhead associated (FHA) domain of CHEK2 protein. FHA domain
is responsible for substrate specificity and this missense variation makes CHEK2
protein less stable and more prone to degradation (Bartek and Lukas 2003).
A numbe r of meta-analyses studies have shown that there is a significant associa-
tion between CHEK2 T470C SNP and increased risk of colorectal cancer (CRC)
[(OR,1.67; 95% CI,1.24–2.26), p ¼ 0.0008] and this significant association holds
true for both sporadic and familial CRC (Han et al. 2013; Liu et al. 2012; Bayram
et al. 2012). CHEK2 1100delC is another CHEK2 polymorphic variant which has
shown a significant association with an increased -risk of familial CRC [(OR, 2.80;
95% CI, 1.74–4.51), P < 0.0001] but not with sporadic CRC (Xiang et al. 2011).
These results establish CHEK2 gene as an important CRC-predisposing gene, which
is capable of increasing CRC risk.
5.3.2 Polymorphisms in Transcription Regulating Genes
5.3.2.1 TP53 (P53) Gene Polymorphisms
Tumor protein p53 (TP53) is a principal tumor suppressor gene, and TP53 mutations
have been frequently reported in almost all the cancers (Whibley et al. 2009). TP53,
a 19 kb gene (chromosomal location, 17p13) consists of 11 exons, encoding a
transcript 2629 bp in size, which translates into TP53 protein containing
393 amino acids (Bojesen and Nordestgaard 2008). TP53 functions as a site-specific
DNA-binding transcription factor, which regulates a number of genes, involved in
vital cellular and pathophysiological processes including cell growth, cell cycle
progression, DNA repair, apoptosis, cell metabolism, stem cell regulation, senes-
cence, invasion and metastasis (Bieging et al. 2014 ). TP53 protein is under regula-
tion of several kinases including ATM, ATR, CHEK1and/or CHEK2, which control
it via phosphorylation under the influence of cellular stresses (Bieging et al. 2014;
Barnoud et al. 2019).
Several SNPs have been reported in coding as well as non-coding regions of
TP53 gene (Whibley et al. 2009; Bojesen and Nordestgaard 2008; Murphy 2006).
Out of these SNPs, two non-synonymous SNPs present in exon 4 (codon 47 and
codon 72) of TP53 gene are the most studied ones, because they induce structural
changes in the protein, and drastically affect the function of this tumor suppressor
protein (Pietsch et al. 2006). Codon 47 SNP (P47S; rs1800371) leads to the
production of missense variant in which proline residue is repla ced by serine
whereas codon 72 SNP (P72R; rs1042522) leads to the production of missense
variant in which proline residue is replaced by arginine (Pietsch et al. 2006; Thomas
et al. 1999; Dumont et al. 2003). The proline residue, which is replaced by serine due
to rs1800 371 SNP at codon 47, is critical for recognition by proline-directed kinases
and this SNP therefore decreases the specificity of TP53 protein as a substrate for
phosphorylation by these kinases (Li et al. 2005). The replacement of proline residue
by arginine due to rs1042 522 SNP at codon 72 leads to a 15-fold increase in the
apoptotic effect of TP53 protein. This occurs in part due to an increased interaction
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of TP53 with BAK, a pro-apoptotic protein, which has a direct association with CRC
risk (Dumont et al. 2003; Barnoud et al. 2019). Even though TP53 plays a critical
role in regulation of several vital cellular functions, recent GWAS and meta-analyses
studies have failed to establish any substantial evidence regarding the association
between TP53 SNPs and increased predisposition to various cancers including CRC
(Barnoud et al. 2019; Tian et al. 2017; Wang et al. 2011). TP53 P47S SNP has,
however, been reported to increase the risk of breast cancer particularly in
pre-menopausal African-American, Saudi, and Jewish women (Basu et al., 2018;
Al-Qasem et al. 2012; Ohayon et al. 2005).
5.3.2.2 MDM2 Gene Polymorphisms
Mouse double minute-2 homolog (MDM2) protein, encoded by MDM2 gene (chro-
mosomal location, 12q14.3–15) is an oncoprotein, which functions as a negative
regulator of TP53 protein and inhibits TP53 mediated transcriptional activation
through recognition of and binding to its N-terminal transactivation domain (Or tiz
et al. 2018; Saadatzadeh et al. 2017; Bieging et al. 2014). MDM2 protein also
functions as an E3 ubiquitin-protein ligase and promotes poly-ubiquitylation
mediated proteasomal degradation of TP53 protein (Saadatzadeh et al. 2017).
The pivotal role played by MDM2 protein in regulating the activity of TP53 has
opened a Pandora’s Box for assessing the role of its genetic variations in contributing
to cancer susceptibility (Ortiz et al. 2018). T309G (rs2279744) SNP in intron 1 of
MDM2 gene which involves substitution of thymine at position 309 by guanine has
been reported to modulate the binding of transcription factor, Sp1 to its consensus
sequence in the promoter of MDM2 gene (Bond et al. 2004). T309G SNP enhances
the affinity of Sp1 to bind to its consensus sequence, which leads to increased
MDM2 gene transactivation and expression and consequently increased activity of
MDM2 protein. Increased MDM2 protein levels in turn lead to decreased TP53
activity (Ortiz et al. 2018; Saadatzadeh et al. 2017; Bieging et al. 2014).
A numbe r of meta-analyses studies have shown that there is a significant associa-
tion between MDM2 T309G SNP and increased risk of colorectal cancer. Most of
the studies have reported that the variant G allele of this SNP increases the risk of
CRC among Asian populations [(OR, 1.21, 95% CI, 1.06–1.39), P ¼ 0.005] (Fu et al.
2013; Qin et al. 2013), but not among Caucasians (Zhang et al. 2015a).
5.3.2.3 VDR Gene Polymorphisms
Vitamin D receptor (VDR) gene, a 75 kb gene (chromosomal location, 12q13.11)
consists of 11 exons and encodes VDR protein containing 427 amino acids. Vitamin
D receptor (Vitamin D3 receptor) protein belongs to nuclear hormone receptor
superfamily (type II nuclear receptor superfamily) of ligand-inducible transcription
factors and contains zinc-finger domain which enables it to interact with the pro-
moter region of the vitamin D responsive genes (Pike and Meyer 2012).
VDR is activated by binding to its ligand, calcitriol [1, 25-dihydroxyvitamin D3
(1, 25(OH)
2
D)]. The binding of calcitriol triggers a conformational change within
the receptor enabling it to exert its transcriptional regulatory function via a two-fold
mechanism—first by releasing the co-repressors bound to it in basal conditions and
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second by recruitment of co-activators especially retinoid X receptor (RXR)
(Christakos et al. 2016;Sánchez-Martínez et al. 2008).
VDR has been shown to regulate the functions of diverse types of genes which
include genes whose products are responsible for cellular division and progression,
cell cycle control, differentiation, apoptosis, inflammation, DNA damage repair, etc.
(Ferrer-Mayorga et al. 2019; Christakos et al. 2016). VDR signaling is involved in
multi-level inhibitory regulation of Wnt signaling pathway, which is directly
involved in the initiation and progression of CRC. Higher expression of VDR
gene in fibroblasts of tumor stroma has shown a significant association with longer
survival in CRC patients (Christakos et al. 2016;Sánchez-Martínez et al. 2008).
Several SNPs identified in VDR gene have shown a significant association with
risk of cancer including colorectal cancer. These SNPs include BsmI (rs1544410,
G > A) SNP, ApaI (rs7975232, G > T) SNP, TaqI (rs731236, T > C) SNP, and FokI
(Met1Lys; rs2228570, T > G) SNP. BsmI and ApaI SNPs are intronic SNPs locat ed
between exons 8 and 9, TaqI SNP results in a synonymous sequence change at codon
352 of VDR gene and FokI SNP leads to replacement of initiator amino acid,
methionine by lysine (Nassiri et al. 2013; Bai et al. 2012). Besides, Cdx
(rs11568820, G > A) SNP located in VDR gene promoter has also been evaluated
for any association with cancer risk (Serrano et al. 2016).
A number of GWAS and meta-analyses studies have shown that only BsmI SNP
can modulate the risk of colorectal cancer and this SNP has been associated with a
decreased risk of CRC (Nassiri et al. 2013; Bai et al. 2012). Various studies have
shown that BsmI SNP can predict risk of colorectal cancer among Caucasian
populations but not among Asians (Yu et al. 2014). FokI SNP has also been
associated with an increased risk of colorectal cancer (Pan et al. 2018).
5.3.2.4 PPARG Gene Polymorphisms
Peroxisome proliferator-activated receptor gamma (PPARG/PPARγ) gene (chromo-
somal location, 3p25.2) consists of 146,989 bases and 8 exons and encodes PPARG
protein containing 505 amino acids (Wang et al. 2006). PPARG is another ligand-
activated nuclear transcription factor, which is involved in activation of gene
expression in response to various exogenous ligands (Liang et al. 2018; Grygiel-
Górniak 2014; Wang et al. 2006).
PPARG is involved in regulation of macronutrient metabolism. It shows a high
expression in adipose tissue and regulates differentiation of adipocytes, lipid metab-
olism, and insulin sensitization (Janani and Ranjitha Kumari 2015). PPRG is found
to play role in several pro-tumorigenic pathways like cell cycle regulation, differen-
tiation, apoptosis, and inflammation (Grygiel-Górniak 2014; Wang et al. 2006).
About 60% of sporadic human CRCs have been reported to have higher expression
of PPARG and 8% of primary CRCs have shown specific LOH mutations in the
PPARG gene (Wang et al. 2006; Sarraf et al. 1999).
Several SNPs have been reported in PPARG gene. Out of these SNPs, the two
most studied SNPs include P12A (Pro12Ala, rs1801282) and C161T (His447His,
rs3856806) (Liang et al. 2018; Lu et al. 2010;Xuetal.2010). PPARG P12A SNP is
important as it causes the reduction of the promoter affinity of PPARG protein by
144 M. Z. Banday et al.
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