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approximately 50% and hence can affect the downstream pathways drastically
(Wang et al. 2006; Janani and Ranjitha Kumari 2015). PPARG P12A SNP has
been associated with a decreased risk of colorectal cancer [(OR, 0.84; 95% CI,
0.72–0.98), P ¼ 0.014] (Xu et al. 2010) and [(OR, 0.88; 95% CI, 0.83–0.94),
P < 0.0001)] (Liang et al. 2018). PPARG C161T SNP has also been associated
with a decreased risk of colorectal cancer [(OR, 0.66; 95% CI 0.44–1.00),
P ¼ 0.05)]. The significant association with a decreas ed colorectal cancer risk has
been observed in Caucasians [(OR, 0.43; 95% CI, 0.26–0.69), P ¼ 0.0006)] but not
in Asians [(OR, 0.95, 95% CI 0.73–1.25), P ¼ 0.72)] (Liang et al. 2018). Therefore,
it would be safe to assume that PPARG SNPs could serve as predictive CRC
biomarkers in Caucasians.
5.3.3 Polymorphisms in DNA Repair Pathway Genes
Cell viability is determined directly by the intactness of the DNA molecule present
within it. As DNA is the central molecule which controls all the processes occurring
within the cell, any damage to it will immediately get reflected on the cell structure
and function. DNA damage results from exposure to various carcinogens including
various chemicals, smoke, UV rays, etc. It usually leads to the activation or increased
expression of proto-oncogenes through gain of function mutations and inactivation
or decreased expression of tumor suppressor genes through loss of function
mutations, which are the two main events responsible for initiation and progression
of carcinogenesis (Fearon 2011; Fearon and Vogelstein 1990). Humans have highly
robust, tightly regulated DNA repair mechanisms, each of which can repair specific
type of DNA damage and include mismatch repair (MMR), base excision repair
(BER), nucleotide excision repair (NER), double-strand break repair (DSBR), and
homologous recombination (HR), and non-homologous end joining (NHEJ)
(Chatterjee and Walker 2017; Sameer et al. 2014). A large number of
polymorphisms including single nucleotide polymorphisms (SNPs) in different
genes involved in regulation and function of DNA repair mechanisms have been
shown to modulate the risk of colorectal cancer. The gene polymorphisms through
their affect on the structure and function of gene and its transcription can modulate
regulation and function of DNA repair genes, which in turn influence the suscepti-
bility to various diseases including cancers such as CRC (Jiraskova et al. 2018;
Sameer and Nissar 2018; Nissar et al. 2015; Nissar et al. 2014).
5.3.3.1 OGG1 Gene Polymorphisms
Human 8-Oxoguanine DNA glycosylase 1 (hOGG1/OGG1) gene (chromosomal
location, 3p25.3) consists of 7 exons and encodes a bifunctional DNA glycosylase
protein, human 8-oxoguanine DNA glycosylase (OGG1), which exists in two
isoforms, α-OGG1 (345 amino acids) and β-OGG1 (424 amino acids) (Shinmura
and Yokota 2001; Hung et al. 2005). OGG1 is involved in the repair of 7, 8-dihydro-
8-oxoguanine or 8-oxoguanine (8-oxoG), a mutagenic lesion which is induced or
produced by reactive oxygen species (ROS) and is used as a marker of cellular
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oxidative stress (Kohno et al. 1998). The presence of 8-oxoguanine results in the
incorporation of adenine instead of cytosine during DNA replication, which causes
GC to TA transversion (Shinmura and Yokota 2001). OGG1 also possesses an
intrinsic AP lyase activity, which allows OGG1 enzyme to cleave phosphodiester
linkage at the DNA lesion site creating a single-st rand break, which is fixed via
short-patch BER pathway (Klungland and Bjelland 2007).
Several SNPs have been reported in OGG1 gene. Out of these SNPs, the C977G
(rs1052133; Ser326Cys) SNP is the most studied in colorectal cancer across differ-
ent populations worldwide (Sameer et al. 2012; Yoshimura et al. 2003 ; Le Marchand
et al. 2002). A number of meta-analyses studies have reported the association of
C977G SNP with an increased risk of colorectal cancer amongst both the Caucasian
and Asian populations [OR range ¼ 1.23–1.49] (Wang et al. 2015; Zhang et al.
2014a; Wei et al. 2011). This establishes that the variant allele of OGG1 exhibits a
lower DNA repair activity and hence could serve as one of the early biomarkers
of CRC.
5.3.3.2 XRCC1 Gene Polymorphisms
X-ray repair cross complementing 1 (XRCC1) gene (chromosomal location,
19q13.31), a 33 kb gene, consists of 17 exons and encodes a transcript, 2.2-kb in
size which translates into XRCC1 protein containing 633 amino acids (Nissar et al.
2014). XRCC1 protein is involved in repair of single-strand breaks in DNA [single-
strand breaks repair (SSBR) pathway] and plays a critical role in base excision repair
(BER) pathway. XRCC1 protein functions as a pivotal scaffolding protein, which
participates in repair of single-strand breaks in DNA through stimulation, promotion,
and stabilization of various proteins involved in DNA repair at the affect ed site
(Nissar et al. 2014). At the site of DNA repair, XRCC1 protein interacts with various
proteins including DNA polymerase beta, poly-(ADP-ribose) polymerase-1 (PARP-
1), DNA ligase III, OGG1 and APE (Caldecott 2008; Brem and Hall 2005).
Several SNPs have been reported in XRCC1 gene. Out of these, three SNPs
represented as C580T (rs1799782) SNP, G839 A (rs25489) SNP, and A1196G
(rs25487) SNP, which affect the coding region have been most extensively studied
in CRC. C580T (rs1799782) SNP affects codon 194 and results in substitution of
arginine by tryptophan, G839A (rs25489) SNP affects codon 280 and results in
substitution of arginine by histidine, and A1196G (rs25487) SNP affects codon
399 and results in substitution of arginine by glutamine.
All these non-synonymous SNPs result in structural changes in XRCC1 protein
affecting its DNA repair activity and lead to increased frequency of genetic errors,
which in turn promotes events, which may lead to carcinogenesis. Two meta-
analysis studies have shown that XRCC1 SNPs are not associated with the risk of
colorectal cancer risk (Liu et al. 2013; Wang et al. 2010). However, a significant
association between XRCC1 C580T SNP and risk of CRC in Han Chinese popula-
tion under recessive model [OR ¼ 1.32] has been reported by another meta-analysis
study (Wang et al. 2016). A significant association between XRCC1 A1196G SNP
and CRC risk in both Asian and Caucasian populations has also been reported
(Forat-Yazdi et al. 2015).
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5.3.3.3 XRCC3 Gene Polymorphisms
X-ray repair cross complementing 3 (XRCC3) gene (chromosomal location,
14q32.33) consists of 10 exons and encodes an important member of RecA/
Rad51-related family of proteins, XRCC3 protein which contains 346 amino
acids. XRCC3 protein plays a critical role in repair of double-strand breaks
(DSBs) in DNA and maintains chromosomal stability through homologous recom-
bination (HR) (Thacker and Zdzienicka 2004). To carry out its DNA repair and
chromosomal stability function, XRCC3 protein inte racts with other proteins includ-
ing RAD51c and XRCC2 and any substantial change in the interaction domain has
been reported to negatively affect the function of this protein (Tebbs et al. 1995).
Several SNPs have been reported in XRCC3 gene. Out of these, non-synonymous
SNP C722T (rs861539, Thr241Met) has been most extensively studied. However,
the association of this SNP with the risk of CRC is not conclusive which limits the
use of this SNP as a predictive biomarker for this disease. Two meta-analysis studies
have reported a significant association between this SNP and risk of colorectal
cancer in both Asian and Caucasian populations (Namazi et al. 2015; Wang and
Zhang 2013) whereas other two meta-analysis studies have reported no such associ-
ation (Zhang et al. 2015b ; Liu et al. 2013).
5.3.3.4 RAD51 Gene Polymorphisms
RAD51 gene (chromosomal location, 15q15.1) consists of 13 exons and encodes
RAD51 protein (RAD51 recombinase) which contains 339 amino acids. RAD51
protein plays a critical role in repair of double-strand breaks (DSBs) in DNA through
homologous recombination (HR) (Thompson and Schild 2001; Wick et al. 1996).
Double-strand breaks (DSBs) severely affect the native structure of DNA, arise due
to continued single-strand breaks, and may result from various endogenous or
exogenous processes (Kowalska-Loth et al. 1998). To carry out its function,
RAD51 protein interacts with various proteins including recombination proteins,
DNA damage sensors, tumor suppressor proteins, and cell cycle regulatory proteins
and apoptosis regulatory proteins (Essers et al. 2002).
Several SNPs have been reported in RAD51 gene out of which G135C
(rs1801320) SNP in the 5
0
-untranslated region (5
0
-UTR) is the most common SNP
(Richardson 2005). In one meta-analysis study, G135C SNP has been associated
with a significantly increased risk of colorectal cancer [OR range, 1.21 to 1.62]
(Eskandari et al. 2017). Another meta-analysis study has reported a significant
association of this SNP with an increased risk of CRC in Caucasian populations
but not Asian populations (Zhang et al. 2014b).
5.3.3.5 XPD (ERCC2) Gene Polymorphisms
Xeroderma pigmentosum complementary D, XPD (excision repair cross-
complementation group 2, ERCC2) gene (chromosomal location, 19q13.32) consists
of 22 exons and encodes XPD (ERCC2) protein, which contains 760 amino acids.
XPD protein belongs to Superfamily two (SF2) helicases and constitutes an essential
subunit of transcription factor IIH (TFIIH) complex that is involved in gene tran-
scription and DNA repair.
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XPD protein possesses 5
0
-3’ DNA helicase activity and DNA-dependent ATPase
activity and serves as a vital mediator of Nucleotide Excision Repair (NER) pathway
(Hoeijimakers et al. 1996; Sung et al. 1993).
Several genetic variations including mutations in XPD gene have been reported to
negatively affect the normal functioning of Nucleotide Excision Repair (NER)
pathway which results from decreased activity of TFIIH complex and lead to defects
in transcription, DNA repair, and apoptotic responses and alter geneti c susceptibility
to various diseases including cancers (Coin et al. 1999; Shen et al. 1998). Out of
these genetic variations, two non-synonymous SNPs, G934A (rs1799793;
Asp312Asn) SNP and A2251C (rs13181; Lys751Gln) SNP have been studied in
many populations. However, various meta-analysis studies have reported no signifi-
cant association between these SNPs and risk of colorectal cancer (Zhang et al. 2019;
Zhang and Mo 2014; Du et al. 2014).
5.3.4 Polymorphisms in Folate Metabolism Genes
Folic acid or folate (vitamin B9) is one of B-group vitamins and structurally consists
of three major components, pteridine ring (2-amino-4-hydroxy-pteridine), p-amino
benzoic acid, and glutamic acid. Folate plays vital role in regeneration of methio-
nine, synthesis of nucleic acids, and in shuttling, and redox reactions of one-carbon
units, which are required for normal cellular metabolism and its regulation (Nazki
et al. 2014). Any insufficiency in folate intake or any aberration in folate metabolism
has been associated with an increased risk of colorectal cancer (Ose et al. 2018).
Folate metabolism (Fig. 5.4) is a complex pathway and involves the coordinated
action of at least 30 different enzymes encoded by different genes scattered all over
the human genome. Out of these, the eight enzymes critical for its proper functioning
include NADPH dependent dihydrofolate reductase (DHFR), C-1-tetrahydrofolate
synthase (C1-THF synthetase), 5,10-Methylenetetrahydrofolate reductase (5,10-
MTHFR), thymidylate synthase (TS), Methionine synthase (MTR), Methionine
synthase reductase (MTRR), cystathionine β-synthase (CBS), and cystathionine
γ-lyase (CTH) (Nazki et al. 2014). The role of genetic variations in three of the
important genes coding for critical enzymes (MTHFR, TS, MTR, and MTRR) in
folate metabolism has been extensively reported to modulate risk of colorectal
cancer among different population across the world (Coppedè et al. 2019; Ose
et al. 2018; Levine et al. 2010; Figueiredo et al. 2013).
5.3.4.1 MTHFR Gene Polymorphisms
Methylenetetrahydrofolate reductase (MTHFR) gene, a 19.3 kb gene (chromosomal
location, 1p36.22) consists of 11 exons and encodes MTHFR protein, which
contains 656 amino acids arranged into multiple domains (Saffroy et al. 2005).
MTHFR protein irreversibly converts 5, 10-methyl tetrahydrofolate (5, 10-MTHF)
to 5-methyltetrahydrofolate (5-MTHF), the primary circulating form of folate and an
important precursor for the synthesis of amino acid, methionine which involves
homocysteine methylation. The amino acid, methionine, in turn is required for the
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synthesis of S-adenosyl methionine (SAM), a universal methyl group donor for a
large number of methyl-transfer reactions including DNA methylation (Cicek et al.
2004; Sharp and Little 2004; Nazki et al. 2014; Figueiredo et al. 2013 ).
Several SNPs have been reported in MTHFR gene. Out of these, A1298C
(rs1801131; Glu429Ala) SNP and C677T (rs1801133; Ala222Val) SNP have been
most extensively studied. MTHFR gene A1298C SNP in exon 7 affects codon
429 and results in substitution of glutamate by alanine whereas MTHFR gene
C677T SNP in exon 4 affects codon 222 and results in substitution of alanine by
valine.
Important enzymes of the folate pathway are shown in the blue shades and the
products in green rectangles. [Abbreviations used: DHFR (Dihydrofolate reductase);
SHMT1 (serine hydroxymethyltransferase 1); B6 (Vitamin B6); MTHFR
(methylenetetrahydrofolate reductase); B2 (vitamin B2); TS (thymidylate synthase);
MTR (methionine synthase); B12 (vitamin B12); MTRR (methionine synthase
reductase); DHF (dihydrofolate); THF (tetrahydrofolate); 5,10-MTHF (5,10-methyl
tetrahydrofolate); 5-MTHF (5-methyltetrahydrofolate); dUMP (deoxyuridine
monophosphate); dTMP (deoxythymidine monophosphate); 10-formyl THF
(10-formyl tetrahydrofolate); SAM (S-adenosyl methionine)].
C677T SNP has been associated with a decreased thermo-stability and reduced
activity of MTHFR enzyme, which leads to hyperhomocysteinemia and low serum
folate levels (Coppedè et al. 2019; Wang et al. 2017b; Friedman et al. 1999).
Fig. 5.4 Schematic diagram showing the metabolism of folate in human body. Important enzymes
of the folate pathway are shown in the pink shades and the products in bluish-green rectangles
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Several studies have reported a significant association of MTHFR C677T SNP
with a decreased risk of colorectal cancer. A meta-analysis study reported a signifi-
cant association between C677T SNP and a decreased risk of colorectal cancer in
overall population [(OR, 0.89; 95% Cl, 0.82–0.97)] and Asian population [(OR,
0.82; 95% Cl, 0.69–0.97)] (Sheng et al. 2012). Another meta-analysis study reported
a significant association between C677T SNP and a decreased risk of colorectal
cancer in Asian population [(OR, 0.80; 95%CI, 0.72–0.89)] and Caucasian popula-
tion [(OR, 0.84; 95%CI, 0.76–0.93)] in recessive genetic model (Zhou et al. 2012a).
A recent meta-analysis has reported that there is no significant association between
MTHFR C677T SNP and risk of colorectal cancer (Rai 2015).
5.3.4.2 TYMS/TS Gene Polymorphisms
Thymidylate synthase (TS) gene (chromosomal location, 18p11.32) consists of
8 exons and encodes thymidylate synthase protein, which contains 313 amino
acids. Thymidylate synthase catalyzes the generation of deoxythymidine
monophosphate (dTMP) from deoxyuridine monophosphate (dUMP). This reaction
uses 5,10-methylenetetrahydrofolate as a methyl group donor and produces
dihydrofolate (DHF) as the by-product, which is used to regenerate tetrahydrofolate
(THF) back with the acti on of dihydrofolate reductase (DHFR) (Nazki et al. 2014).
Because of the ability of thymidylate synthase to synthesize thymidine, one of the
nucleotides required for DNA synthesis, TS often serves as a drug target for various
chemotherapeutic agents, such as 5-fluorouracil (5-FU). Besides, mRNA and protein
expression levels of TS serve as important prognostic indicators for several cancers
(Jakobsen et al. 2005; Jian et al. 2004; Moertel 1994).
A number of different genetic variations in the form of variable number of tandem
repeats (VNRTs) have been reported in thymidylate synthase (TS) gene. Out of
these, 28-bp tandem repeat (rs34743033) and 1494 ins/del (rs34489327) have been
most extensively studied. 28 bp polymorphism present in the 5
0
-untranslated region
(5
0
-UTR region/enhancer region) of the TS gene is known to affect the translational
efficiency of TS mRNA and is present as double-tandem repeat (2R) or a triple-
tandem repeat (3R) (Coppedè et al. 2019; Figueiredo et al. 2013; Jakobsen et al.
2005; Lecomte et al. 1994). It has been shown that homozygous 3R/3R cells over-
expressed TYMS mRNA compared with homozygous 2R/2R cells (Mandola et al.
2003).
TYMS 1494 ins/del (rs34489327) gene polymorphism present in 3
0
-untranslated
region (3
0
-UTR) usually presents as a 6 bp deletion at position 1494 and has been
reported to be significantly associated with the low TYMS mRNA expression in
colorectal cancers (Lenz et al. 2002).
A recent meta-analysis study has reported that TS polymorphism is associated
with a decreased risk of colorectal cancer in a dominant genetic model among
Caucasian population but exhibited a significant association with an increased risk
of gastroesophageal cancer among Asian population (Zhou et al. 2012b).
Furthermore, it has also been shown that TS genotyping can be used to predict the
toxicity to 5-fluorouracil based chemotherapy, which emphasizes its importance to
personalized treatment for patients with CRC (Ose et al. 2018; Lecomte et al. 1994).
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5.3.4.3 MTR Gene Polymorphisms
Methionine synthase/5-methyltetrahydrofolate-homocysteine met hyltransferase
(MTR) gene (chromosomal location, 1q43) consists of 33 exons and encodes
methionine synthase (MS) protein, which contains 1265 amino acids. MS catalyzes
the synthesis of methionine through the transfer of a methyl group from
5-methyltetrahydrofolate (5-MTHF) to homocysteine using vitamin B12 as a cofac-
tor. The amino acid, methionine, in turn is required for the synthesis of S-adenosyl
methionine (SAM), a universal methyl group donor for a large number of methyl-
transfer reactions including DNA methylation (Coppedè et al. 2019; Levine et al.
2010; Cicek et al. 2004; Sharp and Little 2004; Nazki et al. 2014; Figueiredo et al.
2013).
Several SNPs have been reported in MTR gene. Out of these, MTR A2756G
(rs1805087; D919G) SNP, which results in substitution of aspartic acid by glycine
has been extensively studied (Coppedè et al. 2019; Ding et al. 2013). This SNP leads
to decreased enzymatic activity, which results in accumulation of homocysteine and
DNA hypomethylation (Zhou et al. 2012b; Levine et al. 2010). Furthermore,
2756GG genotype has been associated with a decreased frequency of CpG island
hypermethylation in tumor suppressor genes (Paz et al. 2002).
Several studies have evaluated the association of MTR A2756G SNP with risk of
colorectal cancer. A meta-analysis study has reported that MTR A2756G SNP is not
significantly associated with the risk of colorectal cancer. The same study has,
however, reported that through gene–environment interactions, this SNP may be
associated with an increased risk of CRC among heavy smokers (OR, 2.06; 95% CI:
1.32–3.20) and heavy drinkers (OR, 2.00, 95% CI: 1.28–3.09) for G allele carriers
(Ding et al. 2013).
5.3.4.4 MTRR Gene Polymorphisms
Methionine synthase reductase (MTRR) gene (chromosomal location, 5p15.31)
consists of 20 exons and encodes 5-methyltetrahydrofolate-homocysteine
methyltransferase reductase (methionine synthase reductase, MTRR) protein,
which contains 698 amino acids. MTRR protein plays a crucial role in the synthesis
of methionine through regeneration of functional methionine synthase (MTR)
enzyme (Nazki et al. 2014; Friso and Choi 2005).
Several SNPs have been reported in MTRR gene. Out of these, MTRR A66G
(rs1801394; I22M) SNP which results in substitution of isoleucine by methionine
has been extensively studied (Leclerc et al. 1998). This SNP results in altered MTRR
enzymatic activity, which affects DNA methylation and related processes and
therefore has a direct impact on cancer susceptibility (Friso and Choi 2005). Under
normal conditions, MTR and MTRR enzymes carry out remethylation of almost
40% homocysteine methionine. A study has reported a significant association of
MTRR A66G SNP with an increased risk of CRC among Caucasian population
(Zhou et al. 2012a). Another study reported that there is no overall significant
association between MTRR A66G SNP and CRC risk (OR, 0.96–1.05, P ¼ 0.44).
However, a significant association between A allele of this SNP and increased CRC
risk was reported among Asian population (OR, 1.13 P ¼ 0.05). The study
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concluded that this SNP is ethnically associated with CRC risk among Asian
populations (Pabalan et al. 2015).
Several other polymorphisms have been reported in genes involved in processes
linked with folate metabolism. These include SNPs in DNA methyltransferase genes
[DNMT3A -448A > G (rs1550117) SNP & DNMT3B -149C > T (rs2424913)
SNP] and reduced folate carrier gene [SLC19A1/RFC1 80G > A (rs1051266) SNP].
These SNPs have been reported to modulate the risk of various cancers but their
association with risk of colorectal cancer is inconclusive. For example, SLC19A1/
RFC1 80G > A (rs1051266) SNP showed no significant association with risk of
colorectal cancer in population based evaluation [(OR, 1.00; 95% CI, 0.81–1.23) and
clinic based evaluation [(OR, 0.75; 95% CI, 0.44–1.29)] (Figueiredo et al. 2013).
Another study has reported that there is no overall significant association between
DNMT3B -149C > T (rs2424913) SNP and CRC risk. However, this SNP is
associated significantly with an increased risk of colorectal cancer in heterozygote
genetic model [GT vs. TT; (OR, 0.50, 95% CI 0.37–0.69); P ¼ 0.00] and dominant
genetic model [GG + GT vs. TT; (OR, 0.51, 95% CI, 0.38–0.69); P ¼ 0.00]
(Khoram-Abadi et al. 2016).
5.4 Conclusion
Although, the molecular pathogenesis of CRC is well characterized, and the role of
major genes involved in its initiation and development are known. However, with
the advent of genome-wide association study (GWAS), the role of genetic
polymorphisms in driving the carcinogenic mechanisms is becoming more and
more elucidated. Therefore, the role played by the SNPs in the low penetrance
genes has become more solidified, especially of the ones performing the central
role in metabolism, DNA repair, or signal transduction. Furthermore, genetic
polymorphisms have also helped in differentiating the geographical and racial
links in modulating the susceptibility to CRC. But the influence of additional
environmental factors like diet, microbiota, lifestyle, and other geographical factors
needs more in-depth studies. The advancement in the next-generation sequencing
(NGS) is one of the best modalities which not only provides the better understanding
of CRC, its molecular subtypes and molecular pathogenesis but also provides one of
the best ways to develop personalized medicine for the management of CRC. NGS
can be easily and effectively used for the early diagnosis and prognosis of CRC,
identification of novel mutations, identification, and characterization of biomarkers
for targeted therapy for treating CRC. NGS coupled with the CRISPR/Cas9 and
immunotherapy also holds a promise for effective personalized medicine with
minimal side effects.
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