GA GENOTYPE OF THE ARG280HIS POLYMORPHISM ON
THE XRCC1 GENE: GENETIC SUSCEPTIBILITY GENOTYPE
IN DIFFERENTIATED THYROID CARCINOMAS?
Kirnap NG1,*, Tutuncu NB1,2, Yalcin Y2, Cebi HPB2, Tutuncu T2,3, Nar A1, Verdi H2, Atac FB2
*Corresponding Author: Nazlı G. Kirnap, M.D., Department of Endocrinology and Metabolism,
Başkent University Faculty of Medicine, Taskent Caddesi No. 77, Bahcelievler, 06490, Ankara, Turkey.
Tel.: +90-(0)312-203-6868. Fax: +90-(0)312-304-2700. E-mail: kirnapnazli@hotmail.com
page: 73
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DISCUSSION
Carcinogenesis leading to thyroid cancer has a complex
molecular mechanism. The only well-known risk
factor is exposure to radiation. Similar to our cases in the
present study, most patients with thyroid cancer have no
history of radiation exposure. There are many unknown
risk factors for patients exposed to environmental insults,
as well as unidentified thyroid cancer susceptibility genes
[1-3].
Previous studies have reported that XRCC1 gene
poly-morphisms may modify the risk of cancer, including
lung, breast and colorectal cancer [9-11]. In recent years,
there have been several case-control studies addressing
the possible associations between XRCC1 polymorphisms
and DTC. However, most of these studies have yielded
inconsistent results due to limited sample size, different
races and risk factors [12-16].
A report from the USA has reported that the AA genotype
in XRCC1 Arg399Gln polymorphism decreases the
risk of PTC [11], but this association was not demonstrated
in other studies [13,14,17]. In Caucasians, it has
been reported that the AA genotype in XRCC1 Arg399Gln
polymorphism causes a significant decrease in the risk of
DTC [2]. In another study, the AA genotype in XRCC1
Arg399Gln was found to be preventive against thyroid
cancer in mixed races [12], though this was not the case for
Caucasians and Asians [13,14,18]. In a study conducted in
Korea, any genotype frequency in the XRCC1 Arg399Gln
polymorphism was found to be similar in DTC and control
groups, but the AT genotype in XRCC1 Arg194Trp polymorphism
was significantly associated with a decreased
risk of PTC compared to the AA genotype [16]. On the
other hand, another study from the USA reported that the
CT genotype in XRCC1 Arg194Trp polymorphism was
associated with an increased risk of DTC [12]. No association
was found between any genotype in the XRCC1
Arg194Trp polymorphism and DTC by Zhu et al. [15].
Wang et al. [19] showed an association of this genotype
with DTC, especially in smokers and drinkers.
In our case-control study, we found no difference in
any genotype frequencies in Arg194Trp and Arg399Gln
XRCC1 with and without cancer, including subgroups
with different clinical characteristics (obese, Hashimoto’s
thyroiditis, smoking and family history of thyroid cancer).
Among the XRCC1 polymorphisms, only the Arg280His
polymorphism was significantly different between DTC
patients. In the present study, the GA genotype frequency
in XRCC1 Arg280His polymorphism was statistically
higher in the DTC group than in the BTN and healthy
control groups. The GA genotype of Arg280His was seen
in approximately 62.0% of DTC cases, while the AA genotype
was most frequently (90.0%) encountered in cancerfree
cases. Although the XRCC1 Arg280His polymorphism
is also one of the most frequently encountered genotype
revealing an association with DTC in Caucasians [20],
there are also conflicting reports that could not demonstrate
any association with this genotype and thyroid cancer
[2,6,13,21].
Although little is known about the functional effects
of the G>A substitution in codon 280 of exon 9 (Arg→His
in the non synonymous polymorphism in XRCC1), functional
changes in the XRCC1 protein may occur due to the
essence of the amino acid substitutions, thus impairing
DNA repair efficiency or accuracy, consequently contributing
to the risk of cancer. The H280 allele may be dysfunctional,
which can lead to haploinsufficiency, or it may
exert a dominant-negative effect on the Arg280 allele. The
XRCC1 Arg280His is located in proliferating cell nuclear
antigen-binding region [22]. Codon 280 of the XRCC1
polypeptide lies within the apurinic/apyrimidinic endonuclease
(APE)-binding domain. There is a possibility that
the Arg280His SNP could alter the XRCC1 structure, and
its ability to interact with APE [23-25]. A functional study
demonstrated that when human XRCC1 variant proteins
are introduced to XRCC1 mutant Chinese hamster ovary
(CHO) cells, XRCC1 carrying 280His could not rescue the
SSBR deficiency in mutant cells [26].
Despite functional studies revealing the possible
mechanisms through which the XRCC1 Arg280His polymorphism
may lead to cancer development, there are contradicting
results from the epidemiological studies [27-32].
This may be explained by the low effect potential of this
polymorphism in carcinogenesis about the presence of
different molecular and environmental insults to DNA.
Cigarette smoking is associated with the production
of free radical intermediates, which are partly corrected by the involvement of XRCC1. Thus, smoke may interact
with the XRCC1 Arg280His polymorphism to initiate and
promote tumorigenesis [33]. In a study by Wang et al. [19],
the Arg194Trp genotype was associated with increased
DTC, especially in smokers. However, in our study, smoking
was not found to be an additional predisposing risk
factor for cancer in any of the XRCC1 genotypes. This is
probably due to the small number of our thyroid cancer
cases who were smokers.
Association of Hashimoto’s thyroiditis with papillary
thyroid cancer was first reported by Dailey et al. [34] in
1955. More recent studies on this topic revealed contradictory
results [35,36]. There was no association between
the presence of Hashimoto’s thyroiditis and DTC with the
distribution of XRCC1 genotypes in our study.
In our study, we had 19 cases of DTC with a family
history of thyroid cancer. Among those patients, approximately
83.0% revealed a GA genotype of the Arg280His.
There was only one case with a family history of thyroid
cancer in the BTN group that revealed an AA genotype of
XRCC1 Arg280His. Although the GA genotype frequency
of the XRCC1 Arg280His was highest in thyroid cancer
cases, it did not appear specifically in families with thyroid
cancer. Instead, it was encountered frequently in benign
nodular goiter cases without a family history of known
thyroid cancer. This may have been due to low penetrance
alleles. However, it may also have been a consequence of
low dose environmental risk for carcinogenesis in those
carrying the XRCC1 Arg280His genotype and BTN that
end up with benign neoplasms of the thyroid. This issue
should be studied with a sufficient number of goiter cases
with a family history of thyroid cancer.
Our findings also revealed that the CC genotype of
Arg194Trp polymorphism and the GG, GA and AA genotypes
of the Arg399Gln polymorphisms of XRCC1 did not
play a role in thyroid carcinogenesis in our study population.
This finding may not mean that these decrease the risk
of DTC as stated by Akulevich et al. [2], but the presence of
these polymorphisms may help to define a low-risk group
for the development of DTC. Further well-designed studies
involving larger sample sizes and considering different
variables, such as gender, lifestyle, chronic thyroiditis,
smoking, alcohol consumption, and radiation exposure, are
needed to fully elucidate the possible roles and associations
of XRCC1 polymorphisms as DTC susceptibility markers
in specific subgroups of patients.
CONCLUSIONS
Our study demonstrates that the GA genotype in the
XRCC1 Arg280His polymorphism is more frequently encountered
in DTC patients than cancer-free controls. The
GA genotype frequency is also rather high in DTC cases
with a family history of thyroid cancer. Obesity, presence of
Hashimoto’s thyroiditis and smoking, which are commonly
accepted as environmental risk factors for thyroid cancer,
did not appear to affect tumorigenesis in the presence of
the GA genotype in the XRCC1 Arg280His polymorphism.
Acknowledgments. The authors would like to thank
the Department of Endocrinology and the Department of
Medical Biology, Başkent University Faculty of Medicine,
Ankara, Turkey, for the laboratory work. All the authors
contributed to the conception and design of the article, the
acquisition of the data, or the analysis and interpretation
of data, as well as writing the article or the revision of its
content; they have read and approved the final version of
the article before submission. Our work was published
as an electronic poster at the 19th European Congress of
Endocrinology (ECE) Lisbon, Portugal, 20-23 May 2017.
[Endocrine Abstracts, 2017; 49: EP1431. doi: 10.1530/
endoabs.49.EP1431.]
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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