Clin Exp Med DOI 10.1007/s10238-014-0329-y
ORIGINAL ARTICLE
Polymorphisms in DNA repair genes and breast cancer risk in Russian population: a case–control study Alexandra S. Shadrina • Natalia A. Ermolenko • Uljana A. Boyarskikh Tatiana V. Sinkina • Alexandr F. Lazarev • Valentina D. Petrova • Maxim L. Filipenko
•
Received: 29 September 2014 / Accepted: 7 December 2014 Ó Springer-Verlag Italia 2014
Abstract Genetic variation in DNA repair genes can alter an individual’s capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni
Electronic supplementary material The online version of this article (doi:10.1007/s10238-014-0329-y) contains supplementary material, which is available to authorized users. A. S. Shadrina (&) N. A. Ermolenko U. A. Boyarskikh M. L. Filipenko Institute of Chemical Biology and Fundamental Medicine, Lavrentjeva, 8, 630090 Novosibirsk, Russia e-mail: [email protected] A. S. Shadrina U. A. Boyarskikh M. L. Filipenko Novosibirsk State University, Pirogova Street, 2, 630090 Novosibirsk, Russia T. V. Sinkina A. F. Lazarev V. D. Petrova Altai Branch of the Russian Blokhin Cancer Research Centre, Nikitina Street, 77, 656049 Barnaul, Russia M. L. Filipenko Kazan Federal University, Kremlyovskaya street, 18, 420008 Kazan, Republic of Tatarstan, Russia
correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians. Keywords population
DNA repair SNP Breast cancer Russian
Introduction Breast cancer is currently the most common malignancy among females [1] and remains the main cause of cancerrelated death in Russian women older than 40 years [2]. Although the mechanism of breast carcinogenesis is still not fully understood, a variety of risk factors have already been identified, including those directly inducing endogenous and exogenous DNA damage (e.g., high lifelong exposure to estrogens, exposure to ionizing radiation, free radicals, polycyclic aromatic hydrocarbons and aromatic amines, metal compounds and organic solvents) [3–5]. The damage can be repaired by DNA repair system, which plays a critical role in protecting against mutations, maintaining genomic integrity and prevention of carcinogenesis. There are five major DNA repair pathways in mammals: nucleotide excision repair (NER), base excision repair (BER), double-strand break repair, mismatch repair (MMR) and DNA interstrand crosslink repair (ICL repair). The NER pathway repairs bulky lesions such as pyrimidine dimers and other photoproducts and large chemical adducts. DNA adducts that link both strands of the duplex are repaired by the ICL repair pathway [6]. BER is responsible for the repair of small lesions such as oxidized, reduced and alkylated bases, abasic sites, some DNA
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adducts and single-strand breaks. Double-strand breaks are repaired by two pathways—homologous recombination repair (HR) and non-homologous end-joining. MMR is responsible for the correction of replication errors (base– base or insertion–deletion mismatches) [7]. To date, more than 150 DNA repair genes have been described in humans [8]. High-penetrant mutations in some of them cause specific syndromes characterized by the increased incidence of tumors, such as Bloom syndrome and xeroderma pigmentosum, or account for some familiar neoplasms, including familiar breast cancer [9]. It has been proposed that genetic variation in the form of single-nucleotide polymorphisms (SNPs) can also modulate the effectiveness of DNA repair and contribute to the development of cancer. In recent years, a number of studies have been conducted to investigate the association between SNPs in DNA repair genes and the risk of breast cancer in diverse populations. The results obtained have been inconsistent, which could be partially due to ethnic and geographic factors. To our knowledge, no study has been published examining the association of SNPs in DNA repair genes with breast cancer risk in Russian population. Therefore, we aimed to conduct such a study and examined seven common polymorphisms rs25487 (R399Q) in the XRCC1 gene (BER pathway), rs1799793 (D312N) and rs13181 (K751Q) in the ERCC2 gene (NER pathway), rs861539 (T241M) in the XRCC3 gene and rs3218536 (R188H) in the XRCC2 gene (HR pathway), rs1776180 in the EXOI gene (MMR and HR pathways) and rs1042522 (R72P) in the TP53 gene (regulation of NER, BER and HR pathways and cell cycle regulation). We selected these SNPs on the basis of their functional effects observed in previous studies [10–17].
Materials and methods Patients Women with sporadic breast cancer and control women were enrolled during an epidemiological study conducted by the Altai Branch of the N. N. Blokhin Cancer Research Centre of the Russian Academy of Medical Science. All cases and controls were Caucasian Russians, lived in the Altai region of Russia and were enrolled in the study during the same period of time (2006–2009). All the individuals gave signed informed consent, and the study was approved by the local ethics committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. The case group consisted of 672 women aged above 45 years with a histologically confirmed diagnosis of breast cancer (mean age 56.3 ± 7.8 years, range 46–83 years). The hospital-based control group included 672 women with
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no personal or family history of cancer (mean age 61.0 ± 15.7 years, range 19–89 years). DNA isolation Genomic DNA was isolated from leukocytes in venous blood by proteinase K digestion followed by phenol/chloroform extraction and ethanol precipitation. DNA samples were stored at -20 °C in a freezer compartment. Genotyping Genotyping was carried out by real-time PCR allelic discrimination with TaqMan probes. Primers and probes were designed using sequences obtained from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih. gov/), UGENE software (version 1.14, http://ugene.unipro. ru/) and Oligo Analyzer software (version 1.0.3). To optimize PCR conditions, we varied annealing temperatures, the composition of buffer solution and the concentration of primers and probes. PCR conditions enabling the best clustering of samples into groups based on the fluorescent signal differences were considered optimal. PCR was performed in 20 lL reaction volume containing 20–100 ng of genomic DNA, 65 mM Tris–HCl (pH 8.9), 24 mM ammonium sulfate, 3.5 mM MgCl2, 0.05 % Tween 20, 0.2 mM dNTP, 0.3 mM of each primer, 0.1 mM of each probe (Online Resource 1) and 1.0 U of Taq polymerase. PCR thermal cycling conditions were as follows: for XRCC1 rs25487, XRCC2 rs3218536, ERCC2 rs13181, TP53 rs1042522 and EXOI rs1776180, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 60 °C; for XRCC3 rs861539, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 62.5 °C; and for ERCC2 rs1799793, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 66 °C. Amplification procedure was conducted using iCycler iQ5 and CFX96 Thermal Cycler (Bio-Rad, USA). Statistical analysis All statistical analyses were performed using the GenABEL statistical package for the R language (version 2.6.0, http://www.r-project.org, glm function). OR and 95 % CI were estimated by logistic regression analysis adopting codominant, additive, dominant and recessive models of inheritance. All data were adjusted for age. To choose the inheritance model that best fits the data, Akaike’s information criterion was used. The expected frequency of genotypes in the control group was tested for the accordance with Hardy–Weinberg equilibrium using exact test. Differences were considered statistically significant at P \ 0.05.
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To estimate the statistical power of study, genetic power calculator (http://pngu.mgh.harvard.edu/*purcell/gpc/cc2. html) was used.
Results The genotypes of seven polymorphisms in DNA repair genes were determined in the group of Russian women having sporadic breast cancer and in the control group of women without oncological diseases. For all studied SNPs, the distribution of genotypes in the control group was in accordance with Hardy–Weinberg equilibrium (Table 1). In the case group, statistically significant deviation from Hardy–Weinberg equilibrium was observed for the XRCC1 rs25487 polymorphism (P = 0.04). The frequencies of the allele A and the genotype AA of the polymorphism XRCC1 rs25487 (R399Q) in the case group were significantly higher than those in the control group (36 and 15 % vs. 31 and 10 %, Table 1). Variant Table 1 Allele and genotype frequencies in the case and the control groups
rs25487 A allele showed an association with the increased risk of breast cancer assuming all tested inheritance models (additive: OR 1.28, P = 0.005; dominant: OR 1.29, P = 0.03; recessive: OR 1.63, P = 0.008; and co-dominant: genotype AA vs. GG: OR 1.76, P = 0.003, Table 2). The comparison of every model to the most general codominant model indicated that an additive model was the most suitable (Table 2). The frequencies of the allele T and the genotype TT of the ERCC2 rs1799793 (D312N) polymorphism among cases were significantly higher compared with those of the control group (40 and 16 % vs. 36 and 13 %, Table 1). Variant rs1799793 T allele was associated with breast cancer risk (additive model: OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02; and co-dominant model: genotype TT vs. CC: OR 1.43, P = 0.04), and an additive model of inheritance was shown to be the most appropriate. However, after applying Bonferroni correction for multiple testing, the associations turned insignificant (Table 2).
SNP
Genotype/allele
Case
Control
HWEa
HWEb
XRCC1
GG
279 (42.4 %)
271 (48.0 %)
0.04
0.62
rs25487
GA
280 (42.6 %)
236 (41.8 %)
(R399Q)
AA
99 (15.0 %)c
57 (10.1 %)c 0.63
0.93
0.22
0.51
0.08
0.59
0.40
0.71
0.63
0.52
0.05
0.51
d
G[A
A
36 %
31 %d
ERCC2
CC
230 (35.2 %)
273 (41.2 %)
rs1799793
CT
321 (49.1 %)
303 (45.8 %)
(D312N)
TT
103 (15.7 %)e
86 (13.0 %)e
C[T
T
40 %
36 %f
ERCC2
TT
228 (34.5 %)
229 (36.5 %)
rs13181
TG
334 (50.5 %)
293 (46.7 %)
(K751Q)
GG
99 (15.0 %)
105 (16.7 %)
T[G XRCC3
G GG
40 % 285 (42.9 %)
40 % 294 (45.7 %)
P value for deviation of genotype distribution in the case group from the Hardy– Weinberg equilibrium (exact test)
rs861539
GA
284 (42.8 %)
278 (43.2 %)
(T241M)
AA
95 (14.3 %)
72 (11.2 %)
G[A
A
36 %
33 %
XRCC2
GG
594 (90.1 %)
587 (89.5 %)
b
rs3218536
GA
65 (9.9 %)
67 (10.2 %)
(R188H)
AA
0 (0.0 %)
2 (0.3 %)
G[A
A
5%
5%
EXOI
CC
221 (33.5 %)
219 (33.3 %)
rs1776180
CG
316 (48.0 %)
329 (50.0 %)
C[G
GG
122 (18.5 %)
110 (16.7 %)
G
42 %
42 %
TP53
GG
332 (51.6 %)
334 (50.4 %)
rs1042522
GC
246 (38.2 %)
268 (40.4 %)
(R72P) G[C
CC C
66 (10.2 %) 29 %
61 (9.2 %) 29 %
a
P value for deviation of genotype distribution in the control group from the Hardy– Weinberg equilibrium (exact test)
c
Statistically significant difference with P = 0.003
d
Statistically significant difference with P = 0.005
e
Statistically significant difference with P = 0.04
f
Statistically significant difference with P = 0.02
f
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Clin Exp Med Table 2 Association of polymorphisms in DNA repair genes with the risk of breast cancer adopting different models of inheritance SNP
Model of inheritance
XRCC1 rs25487 (R399Q)
Co-dominant
G[A
ERCC2 rs1799793 (D312N) C[T
ERCC2 rs13181 (K751Q) T[G
P
AA versus GG
1.76 (1.21–2.57)
0.003
–
GA versus GG
1.17 (0.92–1.51)
0.21
–
Dominant: AA ? GA versus GG
1.29 (1.02–1.63)
0.03
1,603.2
Recessive: AA versus GG ? GA
1.63 (1.14–2.33)
0.008
1,600.4
Additive: AA versus GA versus GG
1.28 (1.08–1.52)
0.005
1,599.6
TT versus CC
1.43 (1.02–2.02)
0.04
–
CT versus CC
1.26 (0.99–1.60)
0.06
–
Dominant: TT ? CT versus CC
1.30 (1.03–1.63)
0.02
1,771.6
Recessive: TT versus CC ? CT Additive: TT versus CT versus CC
1.26 (0.92–1.73) 1.21 (1.03–1.42)
0.15 0.02
1,774.6 1,771.2
0.96 (0.68–1.35)
0.81
Co-dominant
Co-dominant GG versus TT TG versus TT
XRCC3 rs861539 (T241M) G[A
XRCC2 rs3218536 (R188H) G[A
EXOI rs1776180 C[G
TP53 rs1042522 (R72P) G[C
AICa
OR (95 % CI)
–
1.11 (0.87–1.42)
0.42
Dominant: GG ? TG versus TT
1.07 (0.85–1.35)
0.58
1,726.8
–
Recessive: GG versus TT ? TG
0.90 (0.67–1.23)
0.52
1,726.7
Additive: GG versus TG versus TT
1.00 (0.85–1.18)
0.96
1,727.1
AA versus GG
1.35 (0.95–1.92)
0.10
GA versus GG
1.07 (0.85–1.36)
0.55
Dominant: AA ? GA versus GG
1.13 (0.91–1.41)
0.27
1,773.2
Recessive: AA versus GG ? GA
1.30 (0.93–1.82)
0.12
1,772.0
Additive: AA versus GA versus GG
1.14 (0.97–1.33)
0.12
1,772.0
N/Ab
0.97
GA versus GG Dominant: AA ? GA versus GG
1.04 (0.72–1.50) 1.02 (0.71–1.47)
0.84 0.93
– 1,776.7
Recessive: AA versus GG ? GA
N/Ab
0.97
1,775.0
Additive: AA versus GA versus GG
0.99 (0.69–1.42)
0.97
1,776.7
GG versus CC
1.14 (0.83–1.57)
0.41
CG versus CC
0.98 (0.77–1.25)
0.86
Dominant: GG ? CG versus CC
1.02 (0.81–1.28)
0.87
1,852.1
Recessive: GG versus CC ? CG
1.16 (0.87–1.54)
0.31
1,851.1
Additive: GG versus CG versus CC
1.05 (0.90–1.23)
0.50
1,851.7
Co-dominant – –
Co-dominant AA versus GG
–
Co-dominant – –
Co-dominant CC versus GG
1.12 (0.77–1.64)
0.56
–
GC versus GG
0.92 (0.73–1.16)
0.51
–
Dominant: CC ? GC versus GG
0.96 (0.77–1.19)
0.72
1,825.2
Recessive: CC versus GG ? GC
1.16 (0.80–1.67)
0.43
1,824.8
Additive: CC versus GC versus GG
1.01 (0.85–1.19)
0.94
1,825.4
OR and 95 % CI were adjusted for age. Since overall seven SNPs were tested, the significance threshold after implementation of Bonferroni correction for multiple testing is P = 0.007 P values \ 0.05 are in bold a
The Akaike’s information criterion. The preferred inheritance model is the one with the minimum AIC value
b
Unable to calculate since the AA genotype was absent in the case group
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No statistically significant differences in genotype and allele frequencies and no evidence of association were observed for the remaining SNPs.
Discussion Common polymorphisms in DNA repair genes can alter protein function, resulting in the accumulation of DNA damage and mutations, and contribute to the development of cancer [7]. In our study, we investigated the role of polymorphisms XRCC1 rs25487, ERCC2 rs1799793, ERCC2 rs13181, XRCC3 rs861539, XRCC2 rs3218536, EXOI rs1776180 and TP53 rs1042522 in susceptibility to breast cancer in the population of ethnical Russians. All these SNPs have previously been shown to have functional effects [10–17]. We compared the minor allele frequencies of the studied polymorphisms with the frequencies reported in the dbSNP [18] and in published literature. Allele frequencies found in our population were generally closer to those observed in Caucasian populations than to those seen in Asian and African populations. Variant XRCC1 rs25487 A allele was less frequent in our control group (31 %) than in Caucasians (34–38 % [18–21]), but more frequent than in Asians (20–27 % [18, 22–25], except 31 % in Koreans [26]) and in the populations of African ancestry (11–16 % [18, 20, 27]). The frequency of ERCC2 rs1799793 T allele in our control group was 36 %. This value is close to what was previously observed in Caucasians (31–41 % [18, 28–31]), but higher than in Asians (5–10 % [18, 32, 33]) and Africans (7–13 % [18, 30, 31]). Minor alleles of the polymorphisms ERCC2 rs13181, XRCC3 rs861539 and EXOI rs1776180 were also more common in Russians than in Asians and Africans, but had frequencies close or similar to those reported for Caucasian populations. In our control group, these frequencies were 40, 33 and 42 %, correspondingly, while the reported frequencies for Caucasians were 33–42 % [18, 29, 31, 34], 28–45 % [18, 19, 30, 35, 36] and 39–43 % [17, 18]. Asian populations were previously shown to have allele frequencies of 6–10 % [18, 22, 25, 33], 5–12 % [18, 22, 37] and 29 % [18], and the populations of African ancestry had frequencies of 19–24 % [18, 30, 31], 17–22 % [18, 38] and 32 % [18]. XRCC2 rs3218536 A allele frequency in our control group (5 %) was lower than that in Caucasians (7–11 % [18, 19, 36, 38]), but higher than in Asians (0–6 % [18, 39, 40]) and Africans (0–2 % [18, 38]). TP53 rs1042522 C allele had frequency of 29 % that is higher than in Caucasians (23–26 % [18, 41–43]), but lower than in Asians (35–58 % [18, 22, 43, 44]) and Africans (57–73 % [18, 43]). We revealed an association of the allele A of the polymorphism XRCC1 rs25487 with the increased risk of breast
cancer (Table 2). XRCC1 plays an important role in the BER pathway. It interacts with DNA polymerase b, poly (ADP-ribose) polymerase (PARP) and DNA ligase III to rejoin DNA strand breaks and repair gaps left during BER. XRCC1 mutant cells show a defect in the rejoining of single-strand DNA breaks after exposure to X-rays or alkylating agents and are characterized by substantially high levels of sister chromatid exchanges and chromosomal aberrations [45, 46]. The amino acid substitution Arg399Gln caused by the polymorphism rs25487 is located within the XRCC1 domain responsible for the interaction with PARP [47]. Previously published studies revealed the association of this SNP with various markers of DNA damage. Variant allele carriers displayed higher frequency of sister chromatid exchanges, bleomycin-induced chromosomal breaks, X-ray-induced chromosome deletions, polyphenol, aflatoxin B1 and other DNA adducts than wild type subjects [10–14, 48–50], indicating that XRCC1 rs25487 A allele is associated with defective repair. Our results are consistent with the results of recent meta-analyses, although they observed the increased risk of breast cancer associated with XRCC1 rs25487 mainly in Asian, African and mixed populations [51–55]. It is conceivable that a potential environmental or lifestyle factor specific for Russian or for Asian and African populations modulates the effect of XRCC1 rs25487 polymorphism and makes the association more prominent. We can suppose that the consistency of the results obtained for Russians and Asians could be, at least partly, due to the increased environmental pollution. Russia and other developing Asian countries, such as China and India [56], as well as their neighboring countries, suffer from environmental contamination to a greater extent than do European countries and USA. Asia is now a major contributor to air pollutant emissions on a global scale [57], and Russia’s territory is environmentally stressed in consequence of industrialization of the Soviet Union. Greater exposure to environmental carcinogens could result in the increased probability of cancer development in the XRCC1 rs25487 A allele carriers. Furthermore, we have obtained evidence that ERCC2 rs1799793 T allele increases the risk of developing breast cancer. The association was borderline significant, and the significance disappeared after applying Bonferroni correction (Table 2). Since our study had 80 % statistical power at a 0.05 significance level to detect an OR of 1.25 or greater (adopting additive inheritance model) and only 55 % power to detect the same OR value at a 0.007 significance level, we can speculate that additional studies performed on larger groups are warranted to confirm the observed effect. The ERCC2 gene product has an ATP-dependent DNA helicase activity and is a component of the transcription factor complex TFIIH, which participates in both NER and
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basal transcription. Its function is to open up the DNA helix around the damaged site to allow the excision of the damaged DNA fragment [58]. High-penetrant mutations in the ERCC2 gene cause xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. Polymorphism rs1799793 in the ERCC2 gene leads to the Asp312Asn transition in the ERCC2 protein. It is located outside of the catalytic sites, regulatory and interacting domains [59]. However, several functional studies have demonstrated its influence on individual’s capacity to repair damaged DNA. Au et al. [12] found an association of ERCC2 rs179979 with significant increase in UV light-induced chromatid breaks, whereas Hou et al. [60] observed an increased level of aromatic DNA adducts in subjects with the variant allele. In the study by Wolfe et al. [61], ERCC2 rs1799793 T allele significantly decreased constitutive ERCC2 mRNA levels in lymphocytes of healthy subjects, indicating that this SNP may ultimately affect the level of ERCC2 protein. Nevertheless, Qiao et al. [62] and Hemminki et al. [63] failed to reveal any functional effect of ERCC2 rs1799793. Three recent meta-analyses did not found an association of this polymorphism with breast cancer risk in Caucasians, but observed a protective effect in the subgroups of Asians [59, 64, 65], though the analyzed Asian subgroups comprised only two studies and the sample size was limited. Besides this, Pabalan et al. [59] in their meta-analysis observed the association of ERCC2 rs1799793 T with the increased risk of breast cancer considering the adduct studies. They suggested that this polymorphism may alter the risk in the presence of exposure to DNA damaging agents. In our study, we did not measure the level of DNA adducts or other markers of DNA damage, and it is seems reasonable to take this factor into account in further research. For the rest of the SNPs investigated in our study, no association with breast cancer was found. Thus, it is likely that either these SNPs do not influence breast cancer risk in Russian population or their contribution is small and can be revealed only in larger studies. Alternatively, they can be associated with breast cancer only in combination with different external or internal factors such as exposure to polycyclic aromatic hydrocarbons and other chemicals, ionizing radiation, antioxidant consumption and a chronic stress. Conclusion This study is the first study examining the association of polymorphisms in DNA repair genes with the risk of breast cancer in the Russian population. We revealed the association of variant alleles of two polymorphisms, XRCC1 rs25487 and ERCC2 rs1799793, with increased risk of
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breast cancer, providing evidence for their involvement in the etiology of breast cancer in ethnical Russians. Nevertheless, the association of the ERCC2 rs1799793 T allele was insignificant after applying Bonferroni correction for multiple testing, so larger studies are needed to confirm this result. Other tested SNPs ERCC2 rs13181, XRCC3 rs861539, XRCC2 rs3218536, EXOI rs1776180 and TP53 rs1042522 did not show any association with breast cancer risk. Therefore, they do not play a role in breast cancer susceptibility in Russians, or their effects are too small to be revealed in our study or they influence breast cancer risk only in combination with environmental/lifestyle or other factors. These factors should be taken into account in future studies. Acknowledgments We thank the Altai Branch of the Russian Blokhin Cancer Research Centre group for support during the collection of clinical data. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard All the individuals enrolled in this study gave signed informed consent, and the study was approved by the local ethics committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.
References 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49. doi:10.3322/ caac.20006. 2. Davydov MI, Aksel EM. Cancer statistics in Russia and CIS in 2012. Moscow: Russian Cancer Research Center Publishing Group; 2014. 3. Miller K. Estrogen and DNA damage: the silent source of breast cancer? J Natl Cancer Inst. 2003;95:100–2. doi:10.1093/jnci/95.2. 100. 4. McPherson K, Steel CM, Dixon JM. ABC of breast diseases. Breast cancer—epidemiology, risk factors, and genetics. BMJ. 2000;321:624–8. doi:10.1136/bmj.321.7261.624. 5. Mulware SJ. The mammary gland carcinogens: the role of metal compounds and organic solvents. Int J Breast Cancer. 2013;2013:640851. doi:10.1155/2013/640851. 6. Muniandy PA, Liu J, Majumdar A, Liu S, Seidman MM. DNA interstrand crosslink repair in mammalian cells: step by step. Crit Rev Biochem Mol Biol. 2010;45:23–49. doi:10.1155/2013/ 640851. 7. Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomark Prev. 2002;11:1513–30. 8. Wood RD, Mitchell M, Lindahl T. Human DNA repair genes, 2005. Mutat Res. 2005;577:275–83. doi:10.1016/j.mrfmmm. 2005.03.007. 9. Moses RE. DNA damage processing defects and disease. Annu Rev Genomics Hum Genet. 2001;2:41–68. doi:10.1146/annurev. genom.2.1.41. 10. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts
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11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
and glycophorin A variant frequency. Cancer Res. 1999;59:2557–61. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis. 2000;21:965–71. doi:10.1093/carcin/21.5.965. Au WW, Salama SA, Sierra-Torres CH. Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect. 2003;111:1843–50. doi:10.1289/txg.6632. Matullo G, Palli D, Peluso M, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis. 2001;22:1437–45. doi:10.1093/ carcin/22.9.1437. Vodicka P, Kumar R, Stetina R, et al. Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis. 2004;25:757–63. doi:10.1093/carcin/bgh064. Rafii S, O’Regan P, Xinarianos G, et al. A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet. 2002;11:1433–8. doi:10.1093/ hmg/11.12.1433. Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999;19:1092–100. Nebel A, Flachsbart F, Till A, et al. A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians. Mech Ageing Dev. 2009;130:691–9. doi:10.1016/j.mad. 2009.08.004. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11. doi:10.1093/nar/29.1.308. Loizidou MA, Michael T, Neuhausen SL, et al. Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus. Breast Cancer Res Treat. 2008;112:575–9. doi:10.1007/s10549-007-9881-4. Pachkowski BF, Winkel S, Kubota Y, Swenberg JA, Millikan RC, Nakamura J. XRCC1 genotype and breast cancer: functional studies and epidemiologic data show interactions between XRCC1 codon 280 His and smoking. Cancer Res. 2006;66:2860–8. doi:10.1158/0008-5472. Jelonek K, Gdowicz-Klosok A, Pietrowska M, et al. Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. J Appl Genet. 2010;51:343–52. doi:10.1007/BF03208865. Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y. Genetic polymorphisms involved in carcinogen metabolism and DNA repair and lung cancer risk in a Japanese population. J Thorac Oncol. 2012;7:954–62. doi:10.1097/JTO.0b013e31824de30f. Shu XO, Cai Q, Gao YT, Wen W, Jin F, Zheng W. A populationbased case–control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomark Prev. 2003;12:1462–7. Sangrajrang S, Schmezer P, Burkholder I, et al. Polymorphisms in three base excision repair genes and breast cancer risk in Thai women. Breast Cancer Res Treat. 2008;111:279–88. doi:10.1007/ s10549-007-9773-7. Hsu MS, Yu JC, Wang HW, et al. Synergistic effects of polymorphisms in DNA repair genes and endogenous estrogen exposure on female breast cancer risk. Ann Surg Oncol. 2010;17:760–71. doi:10.1245/s10434-009-0802-0. Kim SU, Park SK, Yoo KY, et al. XRCC1 genetic polymorphism and breast cancer risk. Pharmacogenetics. 2002;12:335–8.
27. Duell EJ, Millikan RC, Pittman GS, et al. Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomark Prev. 2001;10:217–22. 28. Debniak T, Scott RJ, Huzarski T, et al. XPD common variants and their association with melanoma and breast cancer risk. Breast Cancer Res Treat. 2006;98:209–15. doi:10.1007/s10549005-9151-2. 29. Kuschel B, Chenevix-Trench G, Spurdle AB, et al. Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk. Cancer Epidemiol Biomark Prev. 2005;14:1828–31. doi:10.1158/1055-9965.EPI-04-0807. 30. Smith TR, Levine EA, Freimanis RI, et al. Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk. Carcinogenesis. 2008;29:2132–8. doi:10.1093/carcin/bgn193. 31. Mechanic LE, Millikan RC, Player J, et al. Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case–control study. Carcinogenesis. 2006;27:1377–85. doi:10.1093/carcin/ bgi330. 32. Lee SA, Lee KM, Park WY, et al. Obesity and genetic polymorphism of ERCC2 and ERCC4 as modifiers of risk of breast cancer. Exp Mol Med. 2005;37:86–90. doi:10.1038/emm.2005. 12. 33. Song B, Zhu JY, Liu J, et al. Association of gene polymorphisms in the DNA repair gene XPD with risk of non-Hodgkin’s lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008;16:97–100. 34. Jakubowska A, Gronwald J, Menkiszak J, et al. BRCA1-associated breast and ovarian cancer risks in Poland: no association with commonly studied polymorphisms. Breast Cancer Res Treat. 2010;119:201–11. doi:10.1007/s10549-009-0390-5. 35. Forsti A, Angelini S, Festa F, et al. Single nucleotide polymorphisms in breast cancer. Oncol Rep. 2004;11:917–22. 36. Kuschel B, Auranen A, McBride S, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet. 2002;11:1399–407. doi:10.1093/hmg/11.12. 1399. 37. Sangrajrang S, Schmezer P, Burkholder I, et al. The XRCC3 Thr241Met polymorphism and breast cancer risk: a case–control study in a Thai population. Biomarkers. 2007;12:523–32. doi:10. 1080/13547500701395602. 38. Millikan RC, Player JS, Decotret AR, Tse CK, Keku T. Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk. Cancer Epidemiol Biomark Prev. 2005;14:2326–34. doi:10.1158/1055-9965.EPI-05-0186. 39. Lee KM, Choi JY, Kang C, et al. Genetic polymorphisms of selected DNA repair genes, estrogen and progesterone receptor status, and breast cancer risk. Clin Cancer Res. 2005;11:4620–6. doi:10.1158/1078-0432.CCR-04-2534. 40. Luo KQ, Mu SQ, Wu ZX, Shi YN, Peng JC. Polymorphisms in DNA repair genes and risk of glioma and meningioma. Asian Pac J Cancer Prev. 2013;14:449–52. doi:10.7314/APJCP.2013.14.1. 449. 41. Szymanowska A, Jassem E, Dziadziuszko R, et al. Increased risk of non-small cell lung cancer and frequency of somatic TP53 gene mutations in Pro72 carriers of TP53 Arg72Pro polymorphism. Lung Cancer. 2006;52:9–14. doi:10.1016/j.lungcan.2005. 12.007. 42. Popanda O, Edler L, Waas P, et al. Elevated risk of squamouscell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer. 2007;55:25–34. doi:10.1016/j.lungcan.2006.09. 006. 43. Onel KB, Huo D, Hastings D, Fryer-Biggs J, Crow MK, Onel K. Lack of association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian,
123
Clin Exp Med
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
African American, and Asian children and adults. Lupus. 2009;18:61–6. doi:10.1177/0961203308094558. Murata M, Tagawa M, Kimura H, Kakisawa K, Shirasawa H, Fujisawa T. Correlation of the mutation of p53 gene and the polymorphism at codon 72 in smoking-related non-small cell lung cancer patients. Int J Oncol. 1998;12:577–81. doi:10.3892/ ijo.12.3.577. Zdzienicka MZ, van der Schans GP, Natarajan AT, Thompson LH, Neuteboom I, Simons JW. A Chinese hamster ovary cell mutant (EM-C11) with sensitivity to simple alkylating agents and a very high level of sister chromatid exchanges. Mutagenesis. 1992;7:265–9. doi:10.1093/mutage/7.4.265. Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV. Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange. Mol Cell Biol. 1990;10:6160–71. doi:10.1128/MCB. 10.12.6160. Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol. 1998;18:3563–71. Wang Y, Spitz MR, Zhu Y, Dong Q, Shete S, Wu X. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair. 2003;2:901–8. doi:10.1016/ S1568-7864(03)00085-5. Lei Y-C, Hwang S, Chang C-C, et al. Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. Mutat Res. 2002;519:93–101. doi:10.1016/ S1383-5718(02)00127-4. Abdel-Rahman SZ, El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett. 2000;159:63–71. doi:10.1016/S03043835(00)00532-2. Bu T, Liu L, Sun Y, et al. XRCC1 Arg399Gln polymorphism confers risk of breast cancer in American population: a metaanalysis of 10846 cases and 11723 controls. PLoS ONE. 2014;9:e86086. doi:10.1371/journal.pone.0086086. Li H, Ha TC, Tai BC. XRCC1 gene polymorphisms and breast cancer risk in different populations: a meta-analysis. Breast. 2009;18:183–91. doi:10.1016/j.breast.2009.03.008. Saadat M, Ansari-Lari M. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures. Breast Cancer Res Treat. 2009;115:137–44. doi:10. 1007/s10549-008-0051-0.
123
54. Huang Y, Li L, Yu L. XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms in breast cancer risk: a meta-analysis. Mutagenesis. 2009;24:331–9. doi:10.1093/mutage/gep013. 55. Wu K, Su D, Lin K, Luo J, Au WW. XRCC1 Arg399Gln gene polymorphism and breast cancer risk: a meta-analysis based on case–control studies. Asian Pac J Cancer Prev. 2011;12:2237–43. 56. Goss PE, Strasser-Weippl K, Lee-Bychkovsky BL, et al. Challenges to effective cancer control in China, India, and Russia. Lancet Oncol. 2014;15:489–538. doi:10.1016/S1470-2045(14)70029-4. 57. Pakpong P, Wild O, Akimoto H. Air pollution import to and export from East Asia. Handb Environ Chem. 2004;4G:99–130. doi:10.1007/b94525. 58. Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 2001;15:15–23. doi:10.1101/gad.859501. 59. Pabalan N, Francisco-Pabalan O, Sung L, Jarjanazi H, Ozcelik H. Meta-analysis of two ERCC2 (XPD) polymorphisms, Asp312Asn and Lys751Gln, in breast cancer. Breast Cancer Res Treat. 2010;124:531–41. doi:10.1007/s10549-010-0863-6. 60. Hou S-M, Fa¨lt S, Angelini S, et al. The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis. 2002;23:599–603. doi:10.1093/car cin/23.4.599. 61. Wolfe KJ, Wickliffe JK, Hill CE, Paolini M, Ammenheuser MM, Abdel-Rahman SZ. Single nucleotide polymorphisms of the DNA repair gene XPD/ERCC2 alter mRNA expression. Pharmacogenet Genomics. 2007;17:897–905. doi:10.1097/FPC.0b013e3280115e63. 62. Qiao Y, Spitz MR, Shen H, et al. Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. Carcinogenesis. 2002;23:295–9. doi:10.1093/carcin/23.2.295. 63. Hemminki K, Xu G, Angelini S, et al. XPD exon 10 and 23 polymorphisms and DNA repair in human skin in situ. Carcinogenesis. 2001;22:1185–8. doi:10.1093/carcin/22.8.1185. 64. Jiang Z, Li C, Xu Y, Cai S, Wang X. Associations between XPD polymorphisms and risk of breast cancer: a meta-analysis. Breast Cancer Res Treat. 2010;123:203–12. doi:10.1007/s10549-0100751-0. 65. Yao L, Qiu L-X, Yu L, et al. The association between ERCC2 Asp312Asn polymorphism and breast cancer risk: a meta-analysis involving 22,766 subjects. Breast Cancer Res Treat. 2010;123:227–31. doi:10.1007/s10549-010-0754-x.
ORIGINAL ARTICLE
Polymorphisms in DNA repair genes and breast cancer risk in Russian population: a case–control study Alexandra S. Shadrina • Natalia A. Ermolenko • Uljana A. Boyarskikh Tatiana V. Sinkina • Alexandr F. Lazarev • Valentina D. Petrova • Maxim L. Filipenko
•
Received: 29 September 2014 / Accepted: 7 December 2014 Ó Springer-Verlag Italia 2014
Abstract Genetic variation in DNA repair genes can alter an individual’s capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni
Electronic supplementary material The online version of this article (doi:10.1007/s10238-014-0329-y) contains supplementary material, which is available to authorized users. A. S. Shadrina (&) N. A. Ermolenko U. A. Boyarskikh M. L. Filipenko Institute of Chemical Biology and Fundamental Medicine, Lavrentjeva, 8, 630090 Novosibirsk, Russia e-mail: [email protected] A. S. Shadrina U. A. Boyarskikh M. L. Filipenko Novosibirsk State University, Pirogova Street, 2, 630090 Novosibirsk, Russia T. V. Sinkina A. F. Lazarev V. D. Petrova Altai Branch of the Russian Blokhin Cancer Research Centre, Nikitina Street, 77, 656049 Barnaul, Russia M. L. Filipenko Kazan Federal University, Kremlyovskaya street, 18, 420008 Kazan, Republic of Tatarstan, Russia
correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians. Keywords population
DNA repair SNP Breast cancer Russian
Introduction Breast cancer is currently the most common malignancy among females [1] and remains the main cause of cancerrelated death in Russian women older than 40 years [2]. Although the mechanism of breast carcinogenesis is still not fully understood, a variety of risk factors have already been identified, including those directly inducing endogenous and exogenous DNA damage (e.g., high lifelong exposure to estrogens, exposure to ionizing radiation, free radicals, polycyclic aromatic hydrocarbons and aromatic amines, metal compounds and organic solvents) [3–5]. The damage can be repaired by DNA repair system, which plays a critical role in protecting against mutations, maintaining genomic integrity and prevention of carcinogenesis. There are five major DNA repair pathways in mammals: nucleotide excision repair (NER), base excision repair (BER), double-strand break repair, mismatch repair (MMR) and DNA interstrand crosslink repair (ICL repair). The NER pathway repairs bulky lesions such as pyrimidine dimers and other photoproducts and large chemical adducts. DNA adducts that link both strands of the duplex are repaired by the ICL repair pathway [6]. BER is responsible for the repair of small lesions such as oxidized, reduced and alkylated bases, abasic sites, some DNA
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adducts and single-strand breaks. Double-strand breaks are repaired by two pathways—homologous recombination repair (HR) and non-homologous end-joining. MMR is responsible for the correction of replication errors (base– base or insertion–deletion mismatches) [7]. To date, more than 150 DNA repair genes have been described in humans [8]. High-penetrant mutations in some of them cause specific syndromes characterized by the increased incidence of tumors, such as Bloom syndrome and xeroderma pigmentosum, or account for some familiar neoplasms, including familiar breast cancer [9]. It has been proposed that genetic variation in the form of single-nucleotide polymorphisms (SNPs) can also modulate the effectiveness of DNA repair and contribute to the development of cancer. In recent years, a number of studies have been conducted to investigate the association between SNPs in DNA repair genes and the risk of breast cancer in diverse populations. The results obtained have been inconsistent, which could be partially due to ethnic and geographic factors. To our knowledge, no study has been published examining the association of SNPs in DNA repair genes with breast cancer risk in Russian population. Therefore, we aimed to conduct such a study and examined seven common polymorphisms rs25487 (R399Q) in the XRCC1 gene (BER pathway), rs1799793 (D312N) and rs13181 (K751Q) in the ERCC2 gene (NER pathway), rs861539 (T241M) in the XRCC3 gene and rs3218536 (R188H) in the XRCC2 gene (HR pathway), rs1776180 in the EXOI gene (MMR and HR pathways) and rs1042522 (R72P) in the TP53 gene (regulation of NER, BER and HR pathways and cell cycle regulation). We selected these SNPs on the basis of their functional effects observed in previous studies [10–17].
Materials and methods Patients Women with sporadic breast cancer and control women were enrolled during an epidemiological study conducted by the Altai Branch of the N. N. Blokhin Cancer Research Centre of the Russian Academy of Medical Science. All cases and controls were Caucasian Russians, lived in the Altai region of Russia and were enrolled in the study during the same period of time (2006–2009). All the individuals gave signed informed consent, and the study was approved by the local ethics committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. The case group consisted of 672 women aged above 45 years with a histologically confirmed diagnosis of breast cancer (mean age 56.3 ± 7.8 years, range 46–83 years). The hospital-based control group included 672 women with
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no personal or family history of cancer (mean age 61.0 ± 15.7 years, range 19–89 years). DNA isolation Genomic DNA was isolated from leukocytes in venous blood by proteinase K digestion followed by phenol/chloroform extraction and ethanol precipitation. DNA samples were stored at -20 °C in a freezer compartment. Genotyping Genotyping was carried out by real-time PCR allelic discrimination with TaqMan probes. Primers and probes were designed using sequences obtained from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih. gov/), UGENE software (version 1.14, http://ugene.unipro. ru/) and Oligo Analyzer software (version 1.0.3). To optimize PCR conditions, we varied annealing temperatures, the composition of buffer solution and the concentration of primers and probes. PCR conditions enabling the best clustering of samples into groups based on the fluorescent signal differences were considered optimal. PCR was performed in 20 lL reaction volume containing 20–100 ng of genomic DNA, 65 mM Tris–HCl (pH 8.9), 24 mM ammonium sulfate, 3.5 mM MgCl2, 0.05 % Tween 20, 0.2 mM dNTP, 0.3 mM of each primer, 0.1 mM of each probe (Online Resource 1) and 1.0 U of Taq polymerase. PCR thermal cycling conditions were as follows: for XRCC1 rs25487, XRCC2 rs3218536, ERCC2 rs13181, TP53 rs1042522 and EXOI rs1776180, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 60 °C; for XRCC3 rs861539, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 62.5 °C; and for ERCC2 rs1799793, denaturation for 3 min at 96 °C followed by 48 cycles of 8 s at 96 °C and 40 s at 66 °C. Amplification procedure was conducted using iCycler iQ5 and CFX96 Thermal Cycler (Bio-Rad, USA). Statistical analysis All statistical analyses were performed using the GenABEL statistical package for the R language (version 2.6.0, http://www.r-project.org, glm function). OR and 95 % CI were estimated by logistic regression analysis adopting codominant, additive, dominant and recessive models of inheritance. All data were adjusted for age. To choose the inheritance model that best fits the data, Akaike’s information criterion was used. The expected frequency of genotypes in the control group was tested for the accordance with Hardy–Weinberg equilibrium using exact test. Differences were considered statistically significant at P \ 0.05.
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To estimate the statistical power of study, genetic power calculator (http://pngu.mgh.harvard.edu/*purcell/gpc/cc2. html) was used.
Results The genotypes of seven polymorphisms in DNA repair genes were determined in the group of Russian women having sporadic breast cancer and in the control group of women without oncological diseases. For all studied SNPs, the distribution of genotypes in the control group was in accordance with Hardy–Weinberg equilibrium (Table 1). In the case group, statistically significant deviation from Hardy–Weinberg equilibrium was observed for the XRCC1 rs25487 polymorphism (P = 0.04). The frequencies of the allele A and the genotype AA of the polymorphism XRCC1 rs25487 (R399Q) in the case group were significantly higher than those in the control group (36 and 15 % vs. 31 and 10 %, Table 1). Variant Table 1 Allele and genotype frequencies in the case and the control groups
rs25487 A allele showed an association with the increased risk of breast cancer assuming all tested inheritance models (additive: OR 1.28, P = 0.005; dominant: OR 1.29, P = 0.03; recessive: OR 1.63, P = 0.008; and co-dominant: genotype AA vs. GG: OR 1.76, P = 0.003, Table 2). The comparison of every model to the most general codominant model indicated that an additive model was the most suitable (Table 2). The frequencies of the allele T and the genotype TT of the ERCC2 rs1799793 (D312N) polymorphism among cases were significantly higher compared with those of the control group (40 and 16 % vs. 36 and 13 %, Table 1). Variant rs1799793 T allele was associated with breast cancer risk (additive model: OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02; and co-dominant model: genotype TT vs. CC: OR 1.43, P = 0.04), and an additive model of inheritance was shown to be the most appropriate. However, after applying Bonferroni correction for multiple testing, the associations turned insignificant (Table 2).
SNP
Genotype/allele
Case
Control
HWEa
HWEb
XRCC1
GG
279 (42.4 %)
271 (48.0 %)
0.04
0.62
rs25487
GA
280 (42.6 %)
236 (41.8 %)
(R399Q)
AA
99 (15.0 %)c
57 (10.1 %)c 0.63
0.93
0.22
0.51
0.08
0.59
0.40
0.71
0.63
0.52
0.05
0.51
d
G[A
A
36 %
31 %d
ERCC2
CC
230 (35.2 %)
273 (41.2 %)
rs1799793
CT
321 (49.1 %)
303 (45.8 %)
(D312N)
TT
103 (15.7 %)e
86 (13.0 %)e
C[T
T
40 %
36 %f
ERCC2
TT
228 (34.5 %)
229 (36.5 %)
rs13181
TG
334 (50.5 %)
293 (46.7 %)
(K751Q)
GG
99 (15.0 %)
105 (16.7 %)
T[G XRCC3
G GG
40 % 285 (42.9 %)
40 % 294 (45.7 %)
P value for deviation of genotype distribution in the case group from the Hardy– Weinberg equilibrium (exact test)
rs861539
GA
284 (42.8 %)
278 (43.2 %)
(T241M)
AA
95 (14.3 %)
72 (11.2 %)
G[A
A
36 %
33 %
XRCC2
GG
594 (90.1 %)
587 (89.5 %)
b
rs3218536
GA
65 (9.9 %)
67 (10.2 %)
(R188H)
AA
0 (0.0 %)
2 (0.3 %)
G[A
A
5%
5%
EXOI
CC
221 (33.5 %)
219 (33.3 %)
rs1776180
CG
316 (48.0 %)
329 (50.0 %)
C[G
GG
122 (18.5 %)
110 (16.7 %)
G
42 %
42 %
TP53
GG
332 (51.6 %)
334 (50.4 %)
rs1042522
GC
246 (38.2 %)
268 (40.4 %)
(R72P) G[C
CC C
66 (10.2 %) 29 %
61 (9.2 %) 29 %
a
P value for deviation of genotype distribution in the control group from the Hardy– Weinberg equilibrium (exact test)
c
Statistically significant difference with P = 0.003
d
Statistically significant difference with P = 0.005
e
Statistically significant difference with P = 0.04
f
Statistically significant difference with P = 0.02
f
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Clin Exp Med Table 2 Association of polymorphisms in DNA repair genes with the risk of breast cancer adopting different models of inheritance SNP
Model of inheritance
XRCC1 rs25487 (R399Q)
Co-dominant
G[A
ERCC2 rs1799793 (D312N) C[T
ERCC2 rs13181 (K751Q) T[G
P
AA versus GG
1.76 (1.21–2.57)
0.003
–
GA versus GG
1.17 (0.92–1.51)
0.21
–
Dominant: AA ? GA versus GG
1.29 (1.02–1.63)
0.03
1,603.2
Recessive: AA versus GG ? GA
1.63 (1.14–2.33)
0.008
1,600.4
Additive: AA versus GA versus GG
1.28 (1.08–1.52)
0.005
1,599.6
TT versus CC
1.43 (1.02–2.02)
0.04
–
CT versus CC
1.26 (0.99–1.60)
0.06
–
Dominant: TT ? CT versus CC
1.30 (1.03–1.63)
0.02
1,771.6
Recessive: TT versus CC ? CT Additive: TT versus CT versus CC
1.26 (0.92–1.73) 1.21 (1.03–1.42)
0.15 0.02
1,774.6 1,771.2
0.96 (0.68–1.35)
0.81
Co-dominant
Co-dominant GG versus TT TG versus TT
XRCC3 rs861539 (T241M) G[A
XRCC2 rs3218536 (R188H) G[A
EXOI rs1776180 C[G
TP53 rs1042522 (R72P) G[C
AICa
OR (95 % CI)
–
1.11 (0.87–1.42)
0.42
Dominant: GG ? TG versus TT
1.07 (0.85–1.35)
0.58
1,726.8
–
Recessive: GG versus TT ? TG
0.90 (0.67–1.23)
0.52
1,726.7
Additive: GG versus TG versus TT
1.00 (0.85–1.18)
0.96
1,727.1
AA versus GG
1.35 (0.95–1.92)
0.10
GA versus GG
1.07 (0.85–1.36)
0.55
Dominant: AA ? GA versus GG
1.13 (0.91–1.41)
0.27
1,773.2
Recessive: AA versus GG ? GA
1.30 (0.93–1.82)
0.12
1,772.0
Additive: AA versus GA versus GG
1.14 (0.97–1.33)
0.12
1,772.0
N/Ab
0.97
GA versus GG Dominant: AA ? GA versus GG
1.04 (0.72–1.50) 1.02 (0.71–1.47)
0.84 0.93
– 1,776.7
Recessive: AA versus GG ? GA
N/Ab
0.97
1,775.0
Additive: AA versus GA versus GG
0.99 (0.69–1.42)
0.97
1,776.7
GG versus CC
1.14 (0.83–1.57)
0.41
CG versus CC
0.98 (0.77–1.25)
0.86
Dominant: GG ? CG versus CC
1.02 (0.81–1.28)
0.87
1,852.1
Recessive: GG versus CC ? CG
1.16 (0.87–1.54)
0.31
1,851.1
Additive: GG versus CG versus CC
1.05 (0.90–1.23)
0.50
1,851.7
Co-dominant – –
Co-dominant AA versus GG
–
Co-dominant – –
Co-dominant CC versus GG
1.12 (0.77–1.64)
0.56
–
GC versus GG
0.92 (0.73–1.16)
0.51
–
Dominant: CC ? GC versus GG
0.96 (0.77–1.19)
0.72
1,825.2
Recessive: CC versus GG ? GC
1.16 (0.80–1.67)
0.43
1,824.8
Additive: CC versus GC versus GG
1.01 (0.85–1.19)
0.94
1,825.4
OR and 95 % CI were adjusted for age. Since overall seven SNPs were tested, the significance threshold after implementation of Bonferroni correction for multiple testing is P = 0.007 P values \ 0.05 are in bold a
The Akaike’s information criterion. The preferred inheritance model is the one with the minimum AIC value
b
Unable to calculate since the AA genotype was absent in the case group
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No statistically significant differences in genotype and allele frequencies and no evidence of association were observed for the remaining SNPs.
Discussion Common polymorphisms in DNA repair genes can alter protein function, resulting in the accumulation of DNA damage and mutations, and contribute to the development of cancer [7]. In our study, we investigated the role of polymorphisms XRCC1 rs25487, ERCC2 rs1799793, ERCC2 rs13181, XRCC3 rs861539, XRCC2 rs3218536, EXOI rs1776180 and TP53 rs1042522 in susceptibility to breast cancer in the population of ethnical Russians. All these SNPs have previously been shown to have functional effects [10–17]. We compared the minor allele frequencies of the studied polymorphisms with the frequencies reported in the dbSNP [18] and in published literature. Allele frequencies found in our population were generally closer to those observed in Caucasian populations than to those seen in Asian and African populations. Variant XRCC1 rs25487 A allele was less frequent in our control group (31 %) than in Caucasians (34–38 % [18–21]), but more frequent than in Asians (20–27 % [18, 22–25], except 31 % in Koreans [26]) and in the populations of African ancestry (11–16 % [18, 20, 27]). The frequency of ERCC2 rs1799793 T allele in our control group was 36 %. This value is close to what was previously observed in Caucasians (31–41 % [18, 28–31]), but higher than in Asians (5–10 % [18, 32, 33]) and Africans (7–13 % [18, 30, 31]). Minor alleles of the polymorphisms ERCC2 rs13181, XRCC3 rs861539 and EXOI rs1776180 were also more common in Russians than in Asians and Africans, but had frequencies close or similar to those reported for Caucasian populations. In our control group, these frequencies were 40, 33 and 42 %, correspondingly, while the reported frequencies for Caucasians were 33–42 % [18, 29, 31, 34], 28–45 % [18, 19, 30, 35, 36] and 39–43 % [17, 18]. Asian populations were previously shown to have allele frequencies of 6–10 % [18, 22, 25, 33], 5–12 % [18, 22, 37] and 29 % [18], and the populations of African ancestry had frequencies of 19–24 % [18, 30, 31], 17–22 % [18, 38] and 32 % [18]. XRCC2 rs3218536 A allele frequency in our control group (5 %) was lower than that in Caucasians (7–11 % [18, 19, 36, 38]), but higher than in Asians (0–6 % [18, 39, 40]) and Africans (0–2 % [18, 38]). TP53 rs1042522 C allele had frequency of 29 % that is higher than in Caucasians (23–26 % [18, 41–43]), but lower than in Asians (35–58 % [18, 22, 43, 44]) and Africans (57–73 % [18, 43]). We revealed an association of the allele A of the polymorphism XRCC1 rs25487 with the increased risk of breast
cancer (Table 2). XRCC1 plays an important role in the BER pathway. It interacts with DNA polymerase b, poly (ADP-ribose) polymerase (PARP) and DNA ligase III to rejoin DNA strand breaks and repair gaps left during BER. XRCC1 mutant cells show a defect in the rejoining of single-strand DNA breaks after exposure to X-rays or alkylating agents and are characterized by substantially high levels of sister chromatid exchanges and chromosomal aberrations [45, 46]. The amino acid substitution Arg399Gln caused by the polymorphism rs25487 is located within the XRCC1 domain responsible for the interaction with PARP [47]. Previously published studies revealed the association of this SNP with various markers of DNA damage. Variant allele carriers displayed higher frequency of sister chromatid exchanges, bleomycin-induced chromosomal breaks, X-ray-induced chromosome deletions, polyphenol, aflatoxin B1 and other DNA adducts than wild type subjects [10–14, 48–50], indicating that XRCC1 rs25487 A allele is associated with defective repair. Our results are consistent with the results of recent meta-analyses, although they observed the increased risk of breast cancer associated with XRCC1 rs25487 mainly in Asian, African and mixed populations [51–55]. It is conceivable that a potential environmental or lifestyle factor specific for Russian or for Asian and African populations modulates the effect of XRCC1 rs25487 polymorphism and makes the association more prominent. We can suppose that the consistency of the results obtained for Russians and Asians could be, at least partly, due to the increased environmental pollution. Russia and other developing Asian countries, such as China and India [56], as well as their neighboring countries, suffer from environmental contamination to a greater extent than do European countries and USA. Asia is now a major contributor to air pollutant emissions on a global scale [57], and Russia’s territory is environmentally stressed in consequence of industrialization of the Soviet Union. Greater exposure to environmental carcinogens could result in the increased probability of cancer development in the XRCC1 rs25487 A allele carriers. Furthermore, we have obtained evidence that ERCC2 rs1799793 T allele increases the risk of developing breast cancer. The association was borderline significant, and the significance disappeared after applying Bonferroni correction (Table 2). Since our study had 80 % statistical power at a 0.05 significance level to detect an OR of 1.25 or greater (adopting additive inheritance model) and only 55 % power to detect the same OR value at a 0.007 significance level, we can speculate that additional studies performed on larger groups are warranted to confirm the observed effect. The ERCC2 gene product has an ATP-dependent DNA helicase activity and is a component of the transcription factor complex TFIIH, which participates in both NER and
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basal transcription. Its function is to open up the DNA helix around the damaged site to allow the excision of the damaged DNA fragment [58]. High-penetrant mutations in the ERCC2 gene cause xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. Polymorphism rs1799793 in the ERCC2 gene leads to the Asp312Asn transition in the ERCC2 protein. It is located outside of the catalytic sites, regulatory and interacting domains [59]. However, several functional studies have demonstrated its influence on individual’s capacity to repair damaged DNA. Au et al. [12] found an association of ERCC2 rs179979 with significant increase in UV light-induced chromatid breaks, whereas Hou et al. [60] observed an increased level of aromatic DNA adducts in subjects with the variant allele. In the study by Wolfe et al. [61], ERCC2 rs1799793 T allele significantly decreased constitutive ERCC2 mRNA levels in lymphocytes of healthy subjects, indicating that this SNP may ultimately affect the level of ERCC2 protein. Nevertheless, Qiao et al. [62] and Hemminki et al. [63] failed to reveal any functional effect of ERCC2 rs1799793. Three recent meta-analyses did not found an association of this polymorphism with breast cancer risk in Caucasians, but observed a protective effect in the subgroups of Asians [59, 64, 65], though the analyzed Asian subgroups comprised only two studies and the sample size was limited. Besides this, Pabalan et al. [59] in their meta-analysis observed the association of ERCC2 rs1799793 T with the increased risk of breast cancer considering the adduct studies. They suggested that this polymorphism may alter the risk in the presence of exposure to DNA damaging agents. In our study, we did not measure the level of DNA adducts or other markers of DNA damage, and it is seems reasonable to take this factor into account in further research. For the rest of the SNPs investigated in our study, no association with breast cancer was found. Thus, it is likely that either these SNPs do not influence breast cancer risk in Russian population or their contribution is small and can be revealed only in larger studies. Alternatively, they can be associated with breast cancer only in combination with different external or internal factors such as exposure to polycyclic aromatic hydrocarbons and other chemicals, ionizing radiation, antioxidant consumption and a chronic stress. Conclusion This study is the first study examining the association of polymorphisms in DNA repair genes with the risk of breast cancer in the Russian population. We revealed the association of variant alleles of two polymorphisms, XRCC1 rs25487 and ERCC2 rs1799793, with increased risk of
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breast cancer, providing evidence for their involvement in the etiology of breast cancer in ethnical Russians. Nevertheless, the association of the ERCC2 rs1799793 T allele was insignificant after applying Bonferroni correction for multiple testing, so larger studies are needed to confirm this result. Other tested SNPs ERCC2 rs13181, XRCC3 rs861539, XRCC2 rs3218536, EXOI rs1776180 and TP53 rs1042522 did not show any association with breast cancer risk. Therefore, they do not play a role in breast cancer susceptibility in Russians, or their effects are too small to be revealed in our study or they influence breast cancer risk only in combination with environmental/lifestyle or other factors. These factors should be taken into account in future studies. Acknowledgments We thank the Altai Branch of the Russian Blokhin Cancer Research Centre group for support during the collection of clinical data. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard All the individuals enrolled in this study gave signed informed consent, and the study was approved by the local ethics committee. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.
References 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49. doi:10.3322/ caac.20006. 2. Davydov MI, Aksel EM. Cancer statistics in Russia and CIS in 2012. Moscow: Russian Cancer Research Center Publishing Group; 2014. 3. Miller K. Estrogen and DNA damage: the silent source of breast cancer? J Natl Cancer Inst. 2003;95:100–2. doi:10.1093/jnci/95.2. 100. 4. McPherson K, Steel CM, Dixon JM. ABC of breast diseases. Breast cancer—epidemiology, risk factors, and genetics. BMJ. 2000;321:624–8. doi:10.1136/bmj.321.7261.624. 5. Mulware SJ. The mammary gland carcinogens: the role of metal compounds and organic solvents. Int J Breast Cancer. 2013;2013:640851. doi:10.1155/2013/640851. 6. Muniandy PA, Liu J, Majumdar A, Liu S, Seidman MM. DNA interstrand crosslink repair in mammalian cells: step by step. Crit Rev Biochem Mol Biol. 2010;45:23–49. doi:10.1155/2013/ 640851. 7. Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomark Prev. 2002;11:1513–30. 8. Wood RD, Mitchell M, Lindahl T. Human DNA repair genes, 2005. Mutat Res. 2005;577:275–83. doi:10.1016/j.mrfmmm. 2005.03.007. 9. Moses RE. DNA damage processing defects and disease. Annu Rev Genomics Hum Genet. 2001;2:41–68. doi:10.1146/annurev. genom.2.1.41. 10. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts
Clin Exp Med
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
and glycophorin A variant frequency. Cancer Res. 1999;59:2557–61. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis. 2000;21:965–71. doi:10.1093/carcin/21.5.965. Au WW, Salama SA, Sierra-Torres CH. Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect. 2003;111:1843–50. doi:10.1289/txg.6632. Matullo G, Palli D, Peluso M, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis. 2001;22:1437–45. doi:10.1093/ carcin/22.9.1437. Vodicka P, Kumar R, Stetina R, et al. Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis. 2004;25:757–63. doi:10.1093/carcin/bgh064. Rafii S, O’Regan P, Xinarianos G, et al. A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet. 2002;11:1433–8. doi:10.1093/ hmg/11.12.1433. Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999;19:1092–100. Nebel A, Flachsbart F, Till A, et al. A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians. Mech Ageing Dev. 2009;130:691–9. doi:10.1016/j.mad. 2009.08.004. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11. doi:10.1093/nar/29.1.308. Loizidou MA, Michael T, Neuhausen SL, et al. Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus. Breast Cancer Res Treat. 2008;112:575–9. doi:10.1007/s10549-007-9881-4. Pachkowski BF, Winkel S, Kubota Y, Swenberg JA, Millikan RC, Nakamura J. XRCC1 genotype and breast cancer: functional studies and epidemiologic data show interactions between XRCC1 codon 280 His and smoking. Cancer Res. 2006;66:2860–8. doi:10.1158/0008-5472. Jelonek K, Gdowicz-Klosok A, Pietrowska M, et al. Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. J Appl Genet. 2010;51:343–52. doi:10.1007/BF03208865. Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y. Genetic polymorphisms involved in carcinogen metabolism and DNA repair and lung cancer risk in a Japanese population. J Thorac Oncol. 2012;7:954–62. doi:10.1097/JTO.0b013e31824de30f. Shu XO, Cai Q, Gao YT, Wen W, Jin F, Zheng W. A populationbased case–control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomark Prev. 2003;12:1462–7. Sangrajrang S, Schmezer P, Burkholder I, et al. Polymorphisms in three base excision repair genes and breast cancer risk in Thai women. Breast Cancer Res Treat. 2008;111:279–88. doi:10.1007/ s10549-007-9773-7. Hsu MS, Yu JC, Wang HW, et al. Synergistic effects of polymorphisms in DNA repair genes and endogenous estrogen exposure on female breast cancer risk. Ann Surg Oncol. 2010;17:760–71. doi:10.1245/s10434-009-0802-0. Kim SU, Park SK, Yoo KY, et al. XRCC1 genetic polymorphism and breast cancer risk. Pharmacogenetics. 2002;12:335–8.
27. Duell EJ, Millikan RC, Pittman GS, et al. Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomark Prev. 2001;10:217–22. 28. Debniak T, Scott RJ, Huzarski T, et al. XPD common variants and their association with melanoma and breast cancer risk. Breast Cancer Res Treat. 2006;98:209–15. doi:10.1007/s10549005-9151-2. 29. Kuschel B, Chenevix-Trench G, Spurdle AB, et al. Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk. Cancer Epidemiol Biomark Prev. 2005;14:1828–31. doi:10.1158/1055-9965.EPI-04-0807. 30. Smith TR, Levine EA, Freimanis RI, et al. Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk. Carcinogenesis. 2008;29:2132–8. doi:10.1093/carcin/bgn193. 31. Mechanic LE, Millikan RC, Player J, et al. Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case–control study. Carcinogenesis. 2006;27:1377–85. doi:10.1093/carcin/ bgi330. 32. Lee SA, Lee KM, Park WY, et al. Obesity and genetic polymorphism of ERCC2 and ERCC4 as modifiers of risk of breast cancer. Exp Mol Med. 2005;37:86–90. doi:10.1038/emm.2005. 12. 33. Song B, Zhu JY, Liu J, et al. Association of gene polymorphisms in the DNA repair gene XPD with risk of non-Hodgkin’s lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008;16:97–100. 34. Jakubowska A, Gronwald J, Menkiszak J, et al. BRCA1-associated breast and ovarian cancer risks in Poland: no association with commonly studied polymorphisms. Breast Cancer Res Treat. 2010;119:201–11. doi:10.1007/s10549-009-0390-5. 35. Forsti A, Angelini S, Festa F, et al. Single nucleotide polymorphisms in breast cancer. Oncol Rep. 2004;11:917–22. 36. Kuschel B, Auranen A, McBride S, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet. 2002;11:1399–407. doi:10.1093/hmg/11.12. 1399. 37. Sangrajrang S, Schmezer P, Burkholder I, et al. The XRCC3 Thr241Met polymorphism and breast cancer risk: a case–control study in a Thai population. Biomarkers. 2007;12:523–32. doi:10. 1080/13547500701395602. 38. Millikan RC, Player JS, Decotret AR, Tse CK, Keku T. Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk. Cancer Epidemiol Biomark Prev. 2005;14:2326–34. doi:10.1158/1055-9965.EPI-05-0186. 39. Lee KM, Choi JY, Kang C, et al. Genetic polymorphisms of selected DNA repair genes, estrogen and progesterone receptor status, and breast cancer risk. Clin Cancer Res. 2005;11:4620–6. doi:10.1158/1078-0432.CCR-04-2534. 40. Luo KQ, Mu SQ, Wu ZX, Shi YN, Peng JC. Polymorphisms in DNA repair genes and risk of glioma and meningioma. Asian Pac J Cancer Prev. 2013;14:449–52. doi:10.7314/APJCP.2013.14.1. 449. 41. Szymanowska A, Jassem E, Dziadziuszko R, et al. Increased risk of non-small cell lung cancer and frequency of somatic TP53 gene mutations in Pro72 carriers of TP53 Arg72Pro polymorphism. Lung Cancer. 2006;52:9–14. doi:10.1016/j.lungcan.2005. 12.007. 42. Popanda O, Edler L, Waas P, et al. Elevated risk of squamouscell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer. 2007;55:25–34. doi:10.1016/j.lungcan.2006.09. 006. 43. Onel KB, Huo D, Hastings D, Fryer-Biggs J, Crow MK, Onel K. Lack of association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian,
123
Clin Exp Med
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
African American, and Asian children and adults. Lupus. 2009;18:61–6. doi:10.1177/0961203308094558. Murata M, Tagawa M, Kimura H, Kakisawa K, Shirasawa H, Fujisawa T. Correlation of the mutation of p53 gene and the polymorphism at codon 72 in smoking-related non-small cell lung cancer patients. Int J Oncol. 1998;12:577–81. doi:10.3892/ ijo.12.3.577. Zdzienicka MZ, van der Schans GP, Natarajan AT, Thompson LH, Neuteboom I, Simons JW. A Chinese hamster ovary cell mutant (EM-C11) with sensitivity to simple alkylating agents and a very high level of sister chromatid exchanges. Mutagenesis. 1992;7:265–9. doi:10.1093/mutage/7.4.265. Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV. Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange. Mol Cell Biol. 1990;10:6160–71. doi:10.1128/MCB. 10.12.6160. Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol Cell Biol. 1998;18:3563–71. Wang Y, Spitz MR, Zhu Y, Dong Q, Shete S, Wu X. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair. 2003;2:901–8. doi:10.1016/ S1568-7864(03)00085-5. Lei Y-C, Hwang S, Chang C-C, et al. Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. Mutat Res. 2002;519:93–101. doi:10.1016/ S1383-5718(02)00127-4. Abdel-Rahman SZ, El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett. 2000;159:63–71. doi:10.1016/S03043835(00)00532-2. Bu T, Liu L, Sun Y, et al. XRCC1 Arg399Gln polymorphism confers risk of breast cancer in American population: a metaanalysis of 10846 cases and 11723 controls. PLoS ONE. 2014;9:e86086. doi:10.1371/journal.pone.0086086. Li H, Ha TC, Tai BC. XRCC1 gene polymorphisms and breast cancer risk in different populations: a meta-analysis. Breast. 2009;18:183–91. doi:10.1016/j.breast.2009.03.008. Saadat M, Ansari-Lari M. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures. Breast Cancer Res Treat. 2009;115:137–44. doi:10. 1007/s10549-008-0051-0.
123
54. Huang Y, Li L, Yu L. XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms in breast cancer risk: a meta-analysis. Mutagenesis. 2009;24:331–9. doi:10.1093/mutage/gep013. 55. Wu K, Su D, Lin K, Luo J, Au WW. XRCC1 Arg399Gln gene polymorphism and breast cancer risk: a meta-analysis based on case–control studies. Asian Pac J Cancer Prev. 2011;12:2237–43. 56. Goss PE, Strasser-Weippl K, Lee-Bychkovsky BL, et al. Challenges to effective cancer control in China, India, and Russia. Lancet Oncol. 2014;15:489–538. doi:10.1016/S1470-2045(14)70029-4. 57. Pakpong P, Wild O, Akimoto H. Air pollution import to and export from East Asia. Handb Environ Chem. 2004;4G:99–130. doi:10.1007/b94525. 58. Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 2001;15:15–23. doi:10.1101/gad.859501. 59. Pabalan N, Francisco-Pabalan O, Sung L, Jarjanazi H, Ozcelik H. Meta-analysis of two ERCC2 (XPD) polymorphisms, Asp312Asn and Lys751Gln, in breast cancer. Breast Cancer Res Treat. 2010;124:531–41. doi:10.1007/s10549-010-0863-6. 60. Hou S-M, Fa¨lt S, Angelini S, et al. The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis. 2002;23:599–603. doi:10.1093/car cin/23.4.599. 61. Wolfe KJ, Wickliffe JK, Hill CE, Paolini M, Ammenheuser MM, Abdel-Rahman SZ. Single nucleotide polymorphisms of the DNA repair gene XPD/ERCC2 alter mRNA expression. Pharmacogenet Genomics. 2007;17:897–905. doi:10.1097/FPC.0b013e3280115e63. 62. Qiao Y, Spitz MR, Shen H, et al. Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. Carcinogenesis. 2002;23:295–9. doi:10.1093/carcin/23.2.295. 63. Hemminki K, Xu G, Angelini S, et al. XPD exon 10 and 23 polymorphisms and DNA repair in human skin in situ. Carcinogenesis. 2001;22:1185–8. doi:10.1093/carcin/22.8.1185. 64. Jiang Z, Li C, Xu Y, Cai S, Wang X. Associations between XPD polymorphisms and risk of breast cancer: a meta-analysis. Breast Cancer Res Treat. 2010;123:203–12. doi:10.1007/s10549-0100751-0. 65. Yao L, Qiu L-X, Yu L, et al. The association between ERCC2 Asp312Asn polymorphism and breast cancer risk: a meta-analysis involving 22,766 subjects. Breast Cancer Res Treat. 2010;123:227–31. doi:10.1007/s10549-010-0754-x.
