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representation is significant when all four populations are pooled (OR 1.68, 95% CI
1.04–2.71).
The G G C C haplotype includes the G allele of exon 2 and the G allele of exon
13, the two alleles that are associated with an increasing risk in the single locus
analysis. Lesueur et al. observed the strongest association with DTC for
polymorphisms A432A in exon 7 and S836S in exon 14. Nevertheless, the magni-
tude of the observed effect between the RET SNPs and DTC was modest (Lesueur
et al. 2002). SNP S904S gives rise to less frequent codons, so ribosome stalli ng can
happen. In the case of SNP L679L where the codon with higher codon usage
appears, the sheet may not finish creating the structure when the helix appears
(Nakamura et a l. 2007). As a consequence, there is not enough space to create the
appropriate structure. This can lead to changes in kinase activity and/or specificity
and, as a result, influence disease symptoms. These postulated mechanisms are not
mutually exclusive (Maria et al. 2010). The L769L (T > G) variant reduces the
energy of the wild type by 17% and the mutant Y791F by 7%, leading the authors to
conclude that the L769L polymorphism reduces the MFE of small RET mRNA
(Lucieli et al. 2012). The S904S polymorphism does not lead to an amino acid
alteration and because of its co-segregation with G691S, the results obtained with
S904S could be interpreted as a founder effect without influence as genetic modifier,
according to a role of RET S904S as a linked neutral polymorphism, and the main
putative modifier would be the amino acid sequence variant G691S (Robledo et al.
2003). The G691S SNP is synonymous; it has been explained that the G691S variant
occurs in the cytoplasmic tail of the RET amidst transmembrane region and the first
tyrosine kinase domain close to the residue Y687. To explain the G691S polymor-
phism exerting an effect in PTC without activation by RET rearrangement, two
scenarios are possible. Firstly, although RET is not generally believed to be
expressed in thyroid follicular cells (Fabien et al. 1992), it is expressed in the
parafollicular C cells and hence might influence the microenvironment of the
follicular cells. Alternatively, it may be the case that wild-type proto-RET is in fact
expressed in follicular cell tumors as well as parafollicular C cells, as has been
suggested in several recent studies (Fluge et al. 2001).
As a matter of fact, the two amino acids, glycine in the wild-type RET protein and
serine in the polymorphic RET variant, confer different electrochemical and confor-
mational structures to the RET protein, and consequently influence the processing,
folding, subcellular localization, or function of the protein. It has been shown that
polymorphic sequence variants can lead to production of different amounts of
mRNA (Leviev et al. 1997). So, single nucleotide polymorphisms may confer a lot
of changes in RET proto-oncogene at mRNA level or at protein level that deregulates
the MAP kinase or Akt pathway, hence predisposing a person to TC. It may be
suggested that the GGT > AGT polymorphism causes the creation of a cryptic splice
donor, splice acceptor, or splice enhancer, therefore leading to an altered protein that
may contribute to the development of C-cell hyperplasia (Fitze et al. 1999).
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8.4.3 TP53 (Tumor Protein 53)
The human TP53 gene spans about 20 kb of DNA and local ized to the short arm of
chromosome 17 (17p13). This gene is composed of 11 exons, the first of which is
noncoding and localized 8 10 kb away from exons 2 through 11 (Benchimol et al.
1985).
8.4.3.1 Structure and Function of P53 Protein
The human p53 protein consists of 393 amino acids and contains four major
functional domains. At the N terminus is a transcriptional activation domain
(amino acids 1 42) and within the central part of p53 is the sequence-specific
DNA-binding domain (amino acids 102 292). The C-terminal portion contains an
oligomerization domain (amino acids 323 356) and a regulatory domain (amino
acids 360 393) (Pierre and Evelyne 1999).
8.4.3.2 Polymorphisms That Alter the Coding Sequence of p53 Protein
The Serine 47 Polymorphism
The SNP P47S changes an evolutionarily conserved proline residue of p53 to serine.
Initially identified by Felley-Bosco et al., the S47 polymorphic variant is very rare,
with an allele frequency under 5% in African Americans and undetectable in
Caucasians. S47 form of p53 did not affect the growth suppression activity of this
protein as compared to wild-type p53 (P47, or wt) (Felley-Bosco et al. 1993).
The Codon 72 (Arg72Pro) Polymorphism and Its Impact on Cancer Risk
This common SNP (Arg72Pro; rs1042522) results in a non-conservative change of
an arginine (R72) to a proline (P72) at amino acid 72 that results in a structural
change of the protein giving rise to variants of distinct electrophoretic mobility
(Matlashewski et al. 1987). This polymorphism occurs in a proline-rich region of
p53, which is known to be important for the growth suppression and apoptotic
functions of this protein (Sakamuro et al. 1997). Beckman and co-workers were the
first to demonstrate a significant difference in the allelic distribution of the R72 and
P72 variants. They first noted a significant difference in the P72 allele frequency
between a Nigerian population (African Black) and a Swedish population (Western
Europe), which were 17% and 63%, respectively; in contrast, they did not note any
differences between populations living on the same geographical latitude (Beckman
et al. 1994). One of the first studies demonstrated a correlation between the codon
72 polymorphism of TP53 and the risk to cervical cancer wherein they reported that
women with the R72 variant of p53 had a seven-fold increased risk to develop
cervical cancer (Storey et al. 1998).
Several groups have reported an association between the R72 TP53 variant (binds
and inactivates p73 better) and increased risk for epithelial cancer, including gastric
cancer (Shen et al. 2004) and cancer of the breast (Ohayon et al. 2005), ovary
(Pegoraro et al. 2002), esophagus (Kawaguchi et al. 2000), skin (De Oliveira et al.
2004), lung (Wu et al. 2002), bladder (Soulitzis et al. 2002), prost ate (Henner et al.
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2001), and larynx (Sourvinos et al. 2001). In other studies, however, authors have
found the opposite correlation, instead demonstrating an association between the
P72 (lesser apoptotic) variant and increased risk for other cancer types, including
cancer of the thyroid (Granja et al. 2004), nasopharynx (Tiwawech et al. 2003),
prostate (Suzuki et al. 2003), skin (Chen et al. 2003a, b), urogenital region (Kuroda
et al. 2003), and lung (Zhang et al. 2003). Still other groups have failed to demon-
strate any association between codon 72 variants of p53 and cancer risk (Pietsch
et al. 2006).
8.4.3.3 TP53 Gene Polymorphisms in TC
Genetic polymorphisms are reported to be an important cause of the predisposition
to several human cancers including thyroid cancer. The TP53 Arg72Pro
(CGC > CCC; rs1042522) polymorphism of exon 4 (SNP identification number
1042522) has been suggested to play a role in several different cancer types
(Matlashewski et al. 1987). These two variant protein forms may behave differently
(Dumont et al. 2003). To date, only few studies have investigated the association of
codon 72 polymorphism in thyroid tumors (Boltze et al. 2002). They have examined
Caucasian thyroid carcinoma patients, Brazilian population, and Turkish cohort and
concluded that the presence of the proline variant was a potential risk factor for the
induction of thyroid carcinoma and was also associated with a relatively poorer
prognosis. Combined impact of homozygous proline and heterozygous proline/
arginine at codon 72 of TP53 may be a potential risk factor for TC as reported by
the majority of investigations (Yao-Yuan and Chich-Sheng 2006).
Although some previous studies had found only Pro/Pro genotype as a risk factor
for both benign and malignant TCs (Granja et al. 2004) the main factor accounting
for such a discrepancy may be a difference in the genetic back-ground of individuals.
The Arg/Arg genotype has been reported to induce apoptosis more effectively than
the Pro/Pro genotype (Dumont et al. 2003) which may be due to enhanced mito-
chondrial localization of p53 protein in cells with the Arg/Arg genotype (Dumont
et al. 2003). In contrast, the Pro/Pro genotype appears to induce a higher level of G1
arrest than the Arg/Arg genotype probably due to altered binding affinity to p73
(Pietsch et al. 2006). There is a strong association between TC and TP53 Arg72Pro
polymorphism and the TP53 Pro72 homozygotes and heterozygotes are related with
higher susceptibility of TC (Mosin et al. 2015).
8.4.4 XRCC1 (X-Ray Repair Cross-Complementing Protein 1)
This gene is located at 19q13.31, which is the long (q) arm of chromosome 19 at
position 13.31. It extends from base pairs 43,543,311 to 43,575,527 on chromosome
19. The prote in encoded by this gene is involved in the efficient repair of DNA
single-strand breaks formed by exposure to ionizing radiation and alkylating agents.
This protein interacts with DNA ligase III, polymerase beta, and poly (ADP-ribose)
polymerase to participate in the base excision repair pathway (Keith 2019; Nissar
et al. 2014).
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8.4.4.1 XRCC1 Protein Structure
The human gene that encodes XRCC1 was cloned nearly 30 years ago but experi-
mental analysis of this fascinating protein is still unveiling new insights into the
DNA damage response. XRCC1 is a molecular scaffold protein that interacts with
multiple enzymatic components of DNA single-strand break repair (SSBR) includ-
ing DNA kinase, DNA phosphatase, DNA polym erase, DNA deadenylase, and
DNA ligase activities that collectively are capable of accelerating the repair of a
broad range of DNA single-strand breaks (SSBs) (Thompson et al. 1990).
Human XRCC1 is 633 amino acids in length (Thomp son et al. 1990) and is
comprised of a number of protein/molecular interaction domains, and as such is
classified as a molecular scaffold protein (Thompson and West 2000) (Fig. 8.5).
Consistent with this idea, biophysical analyses sugges t that the molecule is asym-
metric with an elongated cigar-shaped structure and axial ratio of >7 (Mani et al.
2004). XRCC1 is comprised of an N-terminal domain (NTD) of ~160 amino acids
that interacts with Pol β (Caldecott et al. 1996), a central BRCT domain of ~90
amino acids that interacts with PARP1 (Masson et al. 1998), PARP2 (Schreiber et al.
2002), poly (ADP-ribose) (Li et al. 2013), and DNA (Mok et al. 2019), and a
C-terminal BRCT domain of ~100 amino acids that binds DNA ligase III (Caldecott
et al. 1994) (Fig. 8.5).
These three domains are separated by two link er domains that contain a nuclear
localization signal and phosphorylation-independent binding site for PNKP (linker
1) (B reslin et al. 2017), and a phosphorylation-dependent binding site for PNKP
(Loizou et al. 2004), APTX (Luo et al. 2004), and APLF (linker 2) (Bekker-Jensen
Fig. 8.5 XRCC1 protein domains and interactions. A cartoon depicting the positio n of XRCC1
protein domains and their molecular interactions. Note that only directly interacting partners of
XRCC1 are shown. Verified interactions are shown above the XRCC1 cartoon and less well-
established and/or weaker interactions are summarized below. XRCC1 is comprised of (left to
right); (1) an amino terminal domain (NTD) that binds directly to POLβ and APEH; (2) a linker
region containing a SUMOylation site (K176) that binds TDG, an RIR-like motif that is part of a
“low-affinity” interaction site for PNKP (see text), and a nuclear localization signal (NLS); (3) a
central BRCT domain (BRCT1) that interacts with poly(ADP-ribose) (green wavy lines, shown
here on PARP1/2) and DNA; (4) a linker region containing three clusters of CK2 phosphorylation
sites (red asterisks), one of which (located at residues 518–523) interacts with PNKP, APTX, and
APLF; (5) a C-terminal BRCT domain (BRCT2) that interacts with LIG3α
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et al. 2007). XRCC1 reportedly also binds a number of additional proteins, the
interactions of which are less defined. A summary of these interactions and their
molecular roles during SSBR is presented in Fig. 8.5.
8.4.4.2 Reported SNPs in the XRCC1 Gene
Although numerous validated SNPs in XRCC1 gene have been identified in the
dbSNP database (http://www.ncbi.nlm.nih.gov/SNP), only three of which are most
widely investigated including Arg194Trp (rs1799782) on exon 6, Arg280His
(rs25489) on exon 9, and Arg399Gln (rs25487) on exon 10 (Shen et al. 1998).
These XRCC1 polymorphisms may affect DNA repair capacity by changing
interactions between XRCC1 protein and other proteins in BER pathway. A large
number of studies have focused on the relationship between XRCC1 polymorphisms
and development of cancer in humans (Tae et al. 2004).
8.4.4.3 TC and XRCC1 Polymorphisms
Over the past decade, several epidemiological studies have reported the association
regarding XRC C1 polymorphisms and TC risk (Zhu et al. 2004; Chiang et al. 2008).
However, the results are to some extent divergent, but nevertheless intriguing.
Previously, two studies by Akulevich et al. (2009) and Ho et al. (2009), respectively,
reported that Arg399Gln (rs25487) polymorphism was associated with decreased
risk of DTC and PTC, whereas Arg399Gln variant genotype carriers presented an
increased risk of PTC in a Chinese study (Zhu et al. 2004). However, more studies
did not support an association between Arg399Gln polymorphism and thyroid
cancer risk (Chiang et al. 2008).
Furthermore, Ho et al. (2009) reported that Arg194Trp variant homozygote
genotype was associated with increased risk of DTC, in agreement with the conclu-
sion by Chiang et al. ( 2008). In contrast, it was reported that the heterozygous
genotype was significantly associated with a decreased risk of PTC in a Korean
population (Ryu et al. 2011). And other studies did not reveal statistically significant
association regarding this polymorphism and thyroid cancer (Fard-Esfahani et al.
2011; Santos et al. 2012). As for Arg280His polymorphism, Garcia-Quispes et al.
(2011) addressed the variant genotype showed a highly increased risk for DTC
among Caucasian, while two studies by Akulevich et al. (2009) and Fard-Esfahani
et al. (2011) found similar trends toward having DTC, but statistical significance was
not attained.
Moreover, another two studies suggested that Arg280His heterozygous genotype
might provide protective effects against the risk of thyroid cancer among Asians, but
this also did not reach statistical significance (Chiang et al. 2008). The discrepancies
across these studies motivated the present meta-analysis. More importantly, many
systematic reviews and meta-analyses have addressed the association of XRCC1
polymorphisms with various cancers (Dai et al. 2009), but have not evaluated the
association between these polymorphisms and TC.
In other words, this is the first meta-analysis undertaken so far of the largest and
most comprehensive assessment for the relationship between XRCC1
polymorphisms and the susceptibility to thyroid cancer. Our meta-analysis did not
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show any significant association between these three polymorphisms (Arg399Gln,
Arg194Trp, and Arg280His) and the risk of DTC in the total population for all
genetic models. Interestingly, in the subgroup analysis by ethnicity, the results
indicated that Arg280His polymorphism was associated with a significantly
increased risk of DTC among Caucasians under dominant genetic model, additive
genetic model, and heterozygote comparison, whereas heterozygote Arg/His geno-
type might provide protective effects in Asians against the risk of DTC. We also
detected that individuals harboring variant allele of Arg399Gln polymorphism might
have a decreased risk of DTC in mixed population, but not in Caucasians or Asians.
In contrast, the Arg194Trp variant allele carriers might have an increased risk of
DTC in mixed population, but not in Caucasians or Asians (Yi et al. 2013).
8.4.5 XRCC3 (X-Ray Repair Cross-Complementing Protein 3) Gene
Located at 14q32.33, which is the long (q) arm of chromosome 14 at position 32.33
and spans base pairs 103,697,611 to 103,715,486 on chromosome 14. This gene is
involved in the homologous recombination repair (HRR) pathway of double-
stranded DNA, thought to repair chromosomal fragmentation, translocations, and
deletions (Kurumizaka et al. 2001).
8.4.5.1 Structure and Function of XRCC3 Protein
XRCC3 is one of the central proteins playing an important role in HRR pathway.
The XRCC3 protein is one of five paralogs of RAD51, including RAD51B
(RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2, and
XRCC3. They each share about 25% amino acid sequence identity with RAD51
and each other. XRCC3 interacts and stabilizes RAD51 and involves in HRR for
DNA DSBs and cross-link repair in mammalian cells (Kurumizaka et al. 2001).
XRCC3 is a paralog of RAD51, and similar to RAD51, it is essential for genetic
stability (Brenneman et al. 2002). Part of the RAD21 paralog protein complex (CX3)
acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, CX3 acts
downstream of RAD51 recruitment; the complex binds predominantly to the inter-
section of the four duplex arms of the Holliday junction (HJ) and to junctions of
replication forks. Involved in HJ resolution and thus in processing HR intermediates
late in the DNA repair process; the function may be linked to the CX3 complex and
seems to involve GEN1 during mitotic cell cycle progression. Part of a PALB2-
scaffolded HR complex containing BRCA2 and RAD51C and which is thought to
play a role in DNA repair by HR. Plays a role in regulating mitochondrial DNA copy
number under conditions of oxidative stress in the presence of RAD51 and RAD51C
(Romana et al. 2017).
8.4.5.2 Polymorphisms in XRCC3 Gene
The Thr241Met (18067C/T, rs861539) is the most common polymorphism of
XRCC3, which substitutes at codon 241 in exon 7, with a C to T transition (Matullo
et al. 2001). Previous studies were performed to investigate the relationship between
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the XRCC3 Thr241Met polymorphism and ovarian cancer risk (Auranen et al.
2005). XRCC3 Thr241Met polymorphism has also been studied in TC wherein
they found homozygous polymorphic genotype (18067TT) to be associated with a
borderline or statistically significant increased risk for DTC (P ¼ 0.05). The homo-
zygous XRCC3 18067TT polymorphic genotype was also found to be associated
with a borderline increased risk for benign thyroid disease (P ¼ 0.052) and this
finding was relatively stable after multivariate adjustment (P ¼ 0.078) (Winsey et al.
2000; Matullo et al. 2001). XRCC3 Thr241Met is the most extensively studied
genetic variant of XRCC3 (Shen et al. 2004) and evidence indicates that the Thr/Met
variant resides in the adenosine triphosphate-binding domain of XRCC3, the only
domain with known functional activity (Manuguerra et al. 2006). This fact suggests
that the change caused by the XRCC3 Thr241Met polymorphism is associated with
other proteins, especially RAD51 (Werbrouck et al. 2009).
In earlier studies, rs1799794 (intron, A > G) polymorphism in XRCC3 has been
associated with increased risk of overall cancer (Han et al. 2006), breast cancer
(He et al. 2012), bladder cancer (Matullo et al. 2005). Finally, rs1799796, an intronic
A > G transition in the XRCC3, was studied in many cancers but the results are
contradictory even in patients suffering from the same type of cancer in different
population. A study from the British population showed that rs1799796 decreases
the risk of breast cancer (Kuschel et al. 2002) while another study from Belgium
reported an increased risk associated with this SNP in BRCA1 and BRCA2 carriers
(Vral et al. 2011). More recently, a significant association with ovarian cancer was
confirmed in a meta-analysis involving Caucasian, Asian, and African populations
(Yuan et al. 2014). On the other hand, studies on ovarian cancer from the British
population (Auranen et al. 2005), lung cancer in Danish population (Jacobsen et al.
2004), bladder and breast cancer in American population (Wu et al. 2006; Han et al.
2004), and prostate and urinary bladder cancer in Indians failed to show any
association with this SNP (Mandal et al. 2010).
8.4.5.3 XRCC3 Polymorphisms and TC
XRCC3 Thr241Met polymorphism (18067C/T, rs861539) has also been studied in
TC wherein they found homozygous polymorphic genotype (18067TT) to be
associated with a borderline or statistically significant increased risk for DTC
(P34 ¼ 0.05) (Erich et al. 2005). Previous studies have reported significant associa-
tion of Thr241Met (rs861539) polymorphism with TC risk (Sturgis et al. 2005;
Bastos et al. 2009). Nevertheless, many studies have found no evident correlation
between XRCC3 polymorphisms and thyroid cancer (Siraj et al. 2008; Akulevich
et al. 2009).
Variant alleles of XRCC3 polymorphisms (rs1799794, rs861539) were found to
increase the risk of TC; however, GG genotype freque ncy of rs1799796 polymor-
phism was found to decrease the TC risk. 3
0
UTR location of rs1799794 SNP can
affect polyadenylation and alterations in regulatory protein–mRNA and miRNA–
mRNA interactions. It can cause disease directly, modifying the severity of the
disease phenotype, or be linked with disease susceptibility (Skeeles et al. 2013).
Fourth studied SNP of XRCC3, rs1799794 (A > G), is locat ed in the 5
0
UTR region
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and significant association of this SNP was observed with increased risk of TC
(Romana et al. 2017). The underlying mechanism of its function may be related to its
alteration in local DNA secondary structure or functional motif, thereby affecting the
binding affinities of the relevant transcription factors (Xu et al. 2012).
8.4.6 The Xeroderma Pigmentosum Group D (XPD) Gene
Also known as excision repair cross-complementation group 2 (ERCC2) gene and
encodes for a 2.3-kb mRNA containing 22 exons and 21 introns. Located at
19q13.32, which is the long (q) arm of chromosome 19 at position 13.32 spanning
the base pairs 45,349,837 to 45,370,647 on chromosome 19. The ERCC2 gene
provides instructions for making a protein called XPD (Benhamou and Sarasin
2002).
8.4.6.1 XPD: Structure and Function
XPD (also known as ERCC2) is a helicase protein of 761 amino acids with a
molecular weight of 86.9 kDa (Benhamou and Sarasin 2002; Sameer and Nissar
2018). XPD is one of the two pivotal ATPase/Helicase of the core unit of THIIF
molecular assembly. It seems to form a bridge between the TFIIH core complex and
the CAK module—which otherwise also exists as a free trimeric complex with its
own distinct functions (Cameroni et al. 2010). XPD belongs to an ATP-dependent
5
0
-3
0
superfamily 2 (SF2) helicases, which are characterized by seven “helicase
motifs” (walker motif I, Ia, II, III, IV, V, and VI) constituted of highly conserved
amino acid sequences (Oksenych and Coin 2010). Interestingly, the XPD protein
also constitutes a 4Fe4S (FeS) cluster that has been demonstrated to be essential for
its helicase activity. Because of this cluster XPD becomes a founding member of a
family of related SF2 helicases (Rudolf et al. 2010). SF2 family helicases also
comprise various importan t family members like bacterial DinG (damage-inducible
G) and the eukaryotic XPD paralogs FancJ (Fanconi’s anemia complementation
group J), RTEL (regular of telomere length), and Chl1 (chromatid cohesion in yeast)
(Wolski et al. 2010; Sameer and Nissar 2018).
The exact function of the FeS cluster is not known but a number of explanations
as to its role have been given like—a purely structural role and providing stabiliza-
tion to the FeS domain; direct interaction with the damaged DNA substrate and
acting as a damage sensor and acting as a regulatory center for XPD helicase
(Houten et al. 2016). Furthermore, XPD serves as the authenticator of the DNA
lesion initially sensed by XPC-HR23B which preludes the binding of TFIIH at the
site of lesion (Oksenych a nd Coin 2010; Coin et al. 2007). The opening of the DNA
duplex at the site of lesion requires the dual ATPase function of both XPB and XPD,
but the helicase activity of XPD plays a critical role in the opening of the DNA. The
biochemical data vividly demonstrated that mutations in the motif I (containing
ATPase activity) of either XPB or XPD inhibit the formation of DNA bubble at the
lesion site but the mutations in the motif III and IV (containing helicase activities) of
XPB impair its functionality but do not inhibit NER in vivo (Coin et al. 1998).
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However, some specific mutations in both XPB and XPD can completely prevent
opening and dual incision of the DNA lesions site in NER (Chen et al. 2003a, b).
Additionally, it has also been demonstrated that binding of N-terminal p44 subunit
with XPD stimulates its helicase activity by almost ten-fold. Furthermore, mutations
in the C-terminal domain (CTD) of XPD prevent the interactions with p44 resulting
not only in decrease in the overall TFIIH helicase activity but also modulate TFIIH
composition and contributing to further transcription defects (Coin et al. 1999). XPD
has also been demonstrated to control the cell cycle via its interaction with CAK
domain of the TFIIH complex. Downregulation of XPD as happens at the beginning
of the mitoses initiates the disengagement of CAK module from TFIIH complex and
its even tual role as regulator of cell cycle independent of TFIIH core complex (Chen
et al. 2003a , b).
8.4.6.2 The XPD Gene and Its SNPs
Apart from point mutations that cause disease, SNPs in the XPD sequence are found
among the general population with a frequency highly variable between 1% and
<50%. Seventeen SNPs in the XPD gene have recently been detected in screening
12 individuals, of which six were found in exons and 11 in introns (Shen et al. 1998).
The coding region polymorphisms include Arg156Arg (rs238406; C156A),
Ile199Met (C199G), Asp312Asn (rs1799793; G312A), and Lys751Gln (rs13181;
A751C). Of these polymorphisms, the frequency of these variant alleles in
Arg156Arg SNP has been estimated to be ~25%. Whereas the Ile199Met SNP is
rare (allele frequency ~4%), the Asp312Asn and Lys751Gln polymorphisms are
common (allele frequencies ~42 and ~29%, respectively) (Shen et al. 1998). Most of
the epidemiological studies on cancer reported to date have focused on SNPs in
codons Arg156Arg 156, Asp312Asn, and Lys751Gln because of their high
frequencies.
The functional significance of these XPD variants has not yet been elucidated, but
some of the variants may be associated with a reduced repair capacity and increased
cancer susceptibility. The 312Asn variant has the acidic moiety of the aspartic acid
removed and the 751Gln variant completely changes the electronic configuration of
the amino acid. This is a major change, located in the important domain of interac-
tion between XPD protein and its helicase activator, p44 protein, inside the TFIIH
complex (Coin et al. 1998). In theory, the consequence of the SNP at amino acid
751 should be the most important in terms of XPD activity.
To the author’s knowledge, seven recent case–control studies have investigated
the effect of XPD polym orphisms on smoking related cancers. Contradictory results
have been observed for the Asp312Asn polymorphism in relation to lung cancer.
The Asn alle le was shown to have a protective effect when compared with the
Asp/Asp genotype in a study of 96 lung cancer cases (Butkiewicz et al. 2001),
whereas it was associated with higher lung cancer risk in the very large study by
Zhou et al. (2002). Regarding the Lys751Gln polymorphism, the homozygous
variant genotype was associated with a higher risk of head and neck cancer (Sturgis
et al. 2000); in contrast, no overall association was found in all the studies on lung
cancer. A protective effect of the Gln allele against basal cell carcinoma was
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suggested when compared with the Lys/Lys genotype in one study (Dybdahl et al.
1999), whereas it was associated with higher risk, although not significantly, in the
other study (Vogel et al. 2001).
The joint effect of these two XPD polymorphisms was investigated in one study,
which revealed a higher risk of lung cancer for individuals carrying two or more
variant alleles (Spitz et al. 2001). Because XPD polymorphisms are presumed to
affect smoking related cancers by repairing DNA damage caused by tobacco
carcinogens, the potential modifying effect of XPD genotype on the relationship
between these cancers and tobacco smoking is of particular interest. Differences in
association for XPD polymorphisms by level of smoking were investigated in some
studies, however, the statistical power to detect them was generally limited and
contradictory results were reported.
Stratified analyses revealed a significant prote ctive effect of the XPD 312Asn
allele against lung cancer in smokers but not in never-smokers in one of the studies
(Butkiewicz et al. 2001), whereas it was associated with an increased risk among
never-smokers only in another study (Hou et al. 2002). A study based on small
sample size suggested that individuals with the A allele of the silent Arg156Arg
polymorphism were at increased risk of basal cell carcinoma (Vogel et al. 2001). In
case of Lys751Gln SNP a protective effect of the Gln allele against basal cell
carcinoma was suggested when compared with the Lys/Lys genotype in one study
(Dybdahl et al. 1999), whereas it was associated with higher risk, although not
significantly, in the other study (Vogel et al. 2001).
8.4.6.3 XPD Polymorphism and TC
Because the ERCC2 gene is involved in the repair of bulky DNA adducts and UV
light-induced DNA damage, various studies have evaluated the role of the ERCC2
Asp312Asn and Lys751Gln polymorphism in exon 10 and 23 in the predisposition
of TC (Ronen and Glickman 2001).
Although several studies have been undertaken to study the role of respective
SNPs but they are not been found associated with TC risk separately (Ronen and
Glickman 2001; Sturgis et al. 2005). The presence of each variant allele leads to a
non-significant increase in the adjusted OR, for all cases and also for papillary and
follicular-type tumors, this effect being more pronounced for the variant form of the
Asp312Asn polymorphism. Both Asp312Asn and Lys751Gln polymorphisms are in
linkage disequilibrium, hence a statistically significant proportion carrying the
variant allele for Asp312Asn also had variant allele for Lys751Gln SNP. According
to a study, subjects homozygous for both variant alleles are over-represented in TC
group and the combination of the two variant forms of both polymorphisms
(Asn312Asn and Gln751Gln) is associated with a significant increase risk to thyroid
cancer suggesting an interaction between these two polymorphisms (Susana et al.
2005).
A significant link of XPD Lys751Gln gene polymorphism with elevated chromo-
some aberrations was observed in TC patients of Ukraine. The average frequency of
chromosome aberrations in patients with genotype Gln751Gln was significantly
higher than in heterozygotes Lys751Gln (Shkarupa et al. 2016).
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