Familial Cancer DOI 10.1007/s10689-015-9787-y
ORIGINAL ARTICLE
Polymorphisms of the XRCC1 gene and breast cancer risk in the Mexican population Nelly M. Macı´as-Go´mez • Valeria Peralta-Leal • Juan Pablo Meza-Espinoza • Melva Gutie´rrez-Angulo • Jorge Dura´n-Gonza´lez • Juan Manuel Ramı´rez-Gonza´lez Alejandra Gaspar-Del Toro • Adolfo Norberto-Rodrı´guez • Evelia Leal-Ugarte
•
Ó Springer Science+Business Media Dordrecht 2015
Abstract The purpose of this case–control study was to evaluate the association of XRCC1 Arg194Trp and Arg399Gln polymorphisms with susceptibility to breast cancer (BC) in a Mexican population. We analysed DNA samples from 345 BC patients and 352 control subjects by polymerase chain reaction-restriction fragment length polymorphism. The frequency of the 399Gln allele was 23 % in controls and 29 % in patients [OR 1.38 (1.08–1.76); p = 0.01]; genotypes in controls were 60, 36, and 4 % for Arg/Arg, Arg/Gln, and Gln/Gln, respectively, while in patients they were 53, 36, and 11 % [OR 2.71 (1.44–5.10); p = 0.0015 for the Gln/Gln genotype]. Regarding the Arg194Trp polymorphism, the frequency of Trp allele was 15 % in controls and 16 % in patients [OR 1.09 (0.82–1.46); p = 0.54]; the genotype frequencies in controls were 74, 23, and 3 % for Arg/Arg, Arg/Trp and
Trp/Trp, respectively, while in patients these were 73, 23, and 4 % [OR 1.41 (0.64–3.14); p = 0.39 for the Trp/Trp genotype]. Allele frequencies were consistent with Hardy– Weinberg equilibrium (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). Our results indicate that the 399Gln polymorphism is associated with an increased risk of BC. Additionally, we found that some covariates increase the risk of BC in Mexican women; namely, antecedent of abortions [OR 3.69 (2.17–6.27); p \ 0.001], not breastfeeding [OR 2.46 (1.45–4.18); p = 0.001], family history of BC [OR 15.9 (5.09–50.23); p \ 0.001], other type of family cancer [OR 31.5 (12.5–79.3); p \ 0.001], alcoholism [OR 17.7 (5.2–60.42); p \ 0.001], type 2 diabetes mellitus [OR 2.28 (1.26–4.10); p = 0.007], and contraceptive use [OR 2.28 (1.26–4.10); p \ 0.001]. Keywords Breast cancer XRCC1 gene Polymorphisms Risk factors
N. M. Macı´as-Go´mez A. Gaspar-Del Toro Departamento de Salud y Bienestar del Centro Universitario del Sur, Universidad de Guadalajara, Cd. Guzma´n, Jal., Mexico V. Peralta-Leal J. P. Meza-Espinoza J. Dura´n-Gonza´lez J. M. Ramı´rez-Gonza´lez E. Leal-Ugarte (&) Facultad de Medicina e Ingenierı´a en Sistemas Computacionales de Matamoros, Universidad Auto´noma de Tamaulipas, Sendero Nacional km 3, C. P. 87349 Matamoros, Tamaulipas, Mexico e-mail: [email protected]; [email protected] M. Gutie´rrez-Angulo Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitla´n de Morelos, Jal., Mexico J. Dura´n-Gonza´lez University of Texas at Brownsville, Brownsville, TX, USA A. Norberto-Rodrı´guez Hospital General ‘‘Alfredo Pumarejo’’, Matamoros, Tamps., Mexico
Introduction Breast cancer (BC) is the most common cause of cancer death and the most prevalent type of cancer in women, with a worldwide incidence of 13 % [1]. In Mexico, BC is considered the second cause of death in women [2]. BC is a multifactorial disease that results from complex interactions between genetic and environmental factors; however, it has been reported that hormonal factors like early age at menarche, late age at menopause, late age at first full term pregnancy, and hormone replacement therapy are the main risk factors for BC development [3]. It has also been suggested that polymorphisms in DNA repair genes may be involved in the aetiology of BC; among the candidates is the XRCC1 gene [4–7]. XRCC1 encodes a protein involved
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in DNA base excision repair (BER), which is 33 kb in length, contains 17 exons and is located at 19q13.2 [8]. More than 60 validated single nucleotide polymorphisms in the XRCC1 gene are listed in the Ensembl database [9]; however, only the non-synonymous polymorphisms rs1799782 (Arg194Trp; C194T) and rs25487 (Arg399Gln; G399A) have been shown to modify DNA repair capacity [10, 11]. The 194Trp variant has been associated with increased BER capacity, whereas the 399Gln variant has been related to a reduced repair capacity [11, 12]. The Arg194Trp polymorphism is located in the linker region separating the NH2-terminal domain from the central BRCT1 (BRCA1 C-terminus) domain. The linker region was also suggested as a potential binding domain of several interactive proteins, and the substitution of Arg to the hydrophobic Trp might affect its binding efficiency. The Arg399Gln polymorphism is located in the BRCT1 domain, which is essential for binding poly [ADP-ribose] polymerase 1. Cells carrying the BCRT1 mutation have been shown to be defective in responding to both X-ray and ultraviolet radiation [13]. Because the XRCC1 polymorphisms may alter DNA repair capacity, a number of studies have attempted to evaluate the impact of these polymorphisms with BC development; however, controversial results have been reported [4–6, 12, 14–31]. Here, we analysed whether there is any association of the XRCC1 polymorphisms Arg194Trp and Arg399Gln with BC in a Mexican population.
Materials and methods A total of 397 patients and 397 controls (cancer-free women) were enrolled; 345 patients and 352 controls had DNA available for genotyping. Patients were enrolled at the Oncology service of the Alfredo Pumarejo Hospital of the Secretary of Health in Matamoros, Tamaulipas Me´xico and from the Secretary of Health in Guzma´n City, Jalisco, along with women with BC who are part of RETO Guadalajara group (no governmental organisation). The mean age of the patients and controls was 47.2 and 50.7 years, respectively, and the average weight was 71 and 68.7 kg, respectively. DNA was extracted from peripheral blood of BC women and healthy women by CTAB–DTAB (denaturing cationic detergents, to precipitate DNA) and Miller (salting out the cellular proteins by dehydration and precipitation with a saturated NaCl solutions) methods. Alleles were detected by PCR–RFLP. The primers used were 50 -GCCCCGTCCCAG GTA-30 and 50 -AGCCCCAAGACCCTTTCACT-30 for Arg194Trp polymorphism, 50 -TTGTGCTTTCTCTGTGTCC A-30 and 50 -TCCTCCAGCCTTTTCTGATA-30 for Arg399Gln. PCR products were 491 and 615 bp,
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respectively. The restriction enzyme used for both polymorphisms was HpaII [32–35]. Allele and genotype frequencies were established by counting and the distribution of genotypes in both groups was compared by Chi square test. Hardy–Weinberg equilibrium (HWE) was evaluated by the Fisher exact test. Association was estimated by odds ratio (OR) and 95 % confidence interval (CI) in SPSS v10.0 software (the wild allele was taken as reference), p \ 0.05 was considered significant. Moreover, each allele and genotype was tested for association with BC risk factors, including BC family and other cancer types, body mass index (BMI), gynaecological and obstetric history, type 2 diabetes mellitus (T2DM), smoking, alcohol and coffee intake. Additionally, each of these variables was analysed between cases and controls to evaluate whether any of them increase the BC risk.
Results The genotype distribution and allele frequency of XRCC1 Arg194Trp and Arg399Gln polymorphisms in BC patients and controls are shown in Table 1. Allele frequencies in controls were consistent with HWE (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). A higher risk of BC was found for the Gln allele [OR 1.38 (1.08–1.76); p = 0.01] and for the Gln/Gln genotype [OR 2.71 (1.44–5.10); p = 0.0015]. However, there was no difference in distribution of the Arg194Trp polymorphism between BC patients and controls [OR 1.09 (0.82–1.46); p = 0.54]. Analysis performed to evaluate the association of variables with genotypes and BC development reported no association. However, in the variables analysis between cases and controls, we observed an increased risk in women who had undergone abortions, did not breastfeed, who had a family history of BC and other types of cancer, who consumed alcohol, used contraceptives, and had concomitant T2DM (Table 2). Age of onset of disease, menarche, menopause, BMI, coffee intake, and smoking showed no differences in this analysis.
Discussion In the present study, we analysed whether the XRCC1 Arg194Trp and Arg399Gln polymorphisms are associated with the risk of BC. Our findings suggest that the Arg399Gln polymorphism is related with an increased risk of BC in Mexican women. This finding agrees with most other similar studies. Dufloth et al. [25] revealed that the Arg399Gln polymorphism might be associated with an increased frequency of BC. Ali et al. [24] also reported that the
Breast cancer risk in the Mexican population Table 1 Genotype distribution and frequency of alleles of Arg194Trp and Arg399Gln polymorphisms of XRCC1 in patients with breast cancer and controls
Genotype/alleles Arg194Trp
Controls n = 352 (%)
Patients n = 345 (%)
Arg/Arg
259 (74)
250 (73)
1.0 (Reference)
Arg/Trp
82 (23)
80 (23)
1.01 (0.71–1.44)
0.95
Trp/Trp
11 (3)
15 (4)
1.41 (0.64–3.14)
0.39 0.74
Arg/Trp ? Trp/Trp
* Chi square test
OR (95 % CI)
p*
93 (26)
95 (28)
1.06 (0.76–1.48)
Arg
600 (85)
580 (84)
1.0 (Reference)
Trp
104 (15)
110 (16)
1.09 (0.82–1.46)
Genotype/alleles Arg399Gln
Controls n = 341 (%)
Patients n = 345 (%)
Arg/Arg
201 (60)
183 (53)
1.0 (Reference)
Arg/Gln
125 (36)
125 (36)
1.10 (0.80–1.51)
0.56
Gln/Gln
15 (4)
37 (11)
2.71 (1.44–5.10)
0.0015 0.12
OR (95 % CI)
Arg/Gln ? Gln/Gln
140 (41)
162 (47)
1.27 (0.94–1.72)
Arg
527 (77)
491 (71)
1.0 (Reference)
Gln
155 (23)
199 (29)
1.38 (1.08–1.76)
Table 2 Clinical variables of risk of breast cancer: logistic regression analysis Abortions
Controls n = 381 (%)
Patients n = 389 (%)
OR (95 % CI)
No
334 (87.7)
278 (71.5)
1.0 (Reference)
Yes
47 (12.3)
111 (28.5)
3.69 (2.17–6.27)
Breast-fed
n = 394 (%)
Yes
311 (78.9)
279 (70.3)
1.0 (Reference)
No
83 (21.1)
118 (29.7)
2.46 (1.45–4.18)
p*
0.001
n = 397 (%)
BC family
n = 397 (%)
n = 397 (%)
2 and 3 degree
392 (98.7)
329 (82.9)
1.0 (Reference)
1 degree
5 (1.3)
68 (17.1)
15.9 (5.09–50.23)
No
389 (98.0)
260 (65.5)
1.0 (Reference)
Yes
8 (2.0)
137 (34.5)
31.5 (12.5–79.3)
No
389 (98.0)
328 (82.6)
1.0 (Reference)
Yes T2DM
8 (2.0)
69 (17.4)
17.7 (5.2–60.42)
No
340 (85.6)
318 (80.1)
1.0 (Reference)
Yes
57 (14.4)
79 (19.9)
2.28 (1.26–4.10)
No
339 (85.4)
209 (52.6)
1.0 (Reference)
Yes
58 (14.6)
188 (47.4)
2.28 (1.26–4.10)
0.001
0.001
Other BC family 0.001
Alcoholism 0.001
0.007
Contraception 0.001
Gln allele was significantly more frequent in BC cases than in controls. Saadat et al. [4] reported that the Gln/Gln genotype significantly increased the risk of BC [OR 2.01
0.54 p*
0.01
(1.02–3.94); p = 0.041]. Likewise, Sterpone et al. [6] found association of Arg/Gln heterozygous and Gln/Gln homozygous with BC [OR 4.8 (1.56–14.78); p = 0.007, and OR 4.4 (1.13–17.1); p = 0.005, respectively]. Equally, Saadat et al. [5] conducted a meta-analysis with 43,716 subjects (20,837 patients and 22,879 controls) of different populations, such as Asian, European, American and Australian. They reported no association of XRCC1 genotypes with BC, but when the sample was stratified by ethnicity, the population from Asian countries with the Gln/Gln genotype had an increased BC risk. Recently, Wu et al. [29] performed a meta-analysis with 20,841 cases and 22,688 controls for Arg399Gln with three ethnic categories: Caucasian, Asian, and African; they concluded that the XRCC1 399Gln allele is a risk factor for BC development, especially among Asian (recessive model) and African (dominant model) populations [OR 1.54 (1.18–2.01) and OR 1.30 (1.07–1.60) respectively]. However, several studies showed no association between the 399Gln allele and BC risk when this allele was analysed without considering other covariates [14–16, 19–23, 26–28, 31]. In contrast, the Arg194Trp polymorphism did not show a significant association with BC in our analysis, in accordance with some studies [12, 15, 19, 22], but not with others; for example, Przybylowska-Sygut et al. [31] found a higher risk of BC for the Trp allele [OR 1.84 (1.16–2.95); p = 0.009] and for the Arg194Trp genotype [OR 1.91 (1.15–3.14); p = 0.011]. Likewise, Al et al. [30] reported association of 194Trp with BC [OR 4.26 (1.40–12.98); p = 0.006] and with the Arg/Trp genotype [OR 4.57 (1.47–14.21); p = 0.005]. On the other hand, we did not find any evidence that XRCC1 genotypes in combination with variables that could
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induce DNA damage or oxidative stress increase the BC risk; these variables include smoking, obesity, alcohol or coffee intake. However, in other studies, a major risk was observed when polymorphisms were combined with covariates [7, 16–19, 23, 36]. Instead, independent of genotype, we observed an increased BC risk in women who had undergone at least one abortion, who did not breastfeed, had a family history of BC and other types of cancer, consumed alcohol, used contraceptives, and had concomitant T2DM. Some studies have suggested that breastfeeding has a protective effect against BC [37–42], while others reported that it is unlikely to be protective [43, 44]. However, Thyagarajan et al. [20] reported no association between several variables and BC, including age at menarche, age at menopause, hormone replacement therapy, female history of cancer, age at first live birth, alcohol intake, smoking status, and waist-to-hip ratio. It has been well documented that hormonal factors are the most important factor involved in BC development, due to it being a hormonal tumour; in this sense, it is well known that pregnancy is a protective factor, and it has been estimated that every pregnancy reduces the risk of BC development by 7 % with respect to nulliparous women. Regarding abortion, it has been suggested that interrupted pregnancy is a risk factor because in the first weeks of pregnancy, the epithelial cells of mama experienced accelerated mitosis, but this is not followed by a differentiation stage; however, the results still are contradictory. In our study, we observed that having an abortion history is a risk factor for BC, but other studies have proposed that therapeutic abortion has a modest protective effect in patients with mutations in the BRCA2 gene [45]. Ilic et al. [46] reported that BC risk was reduced among women who had a history of any abortion OR 0.46 (0.24–0.88) the protective effect was found for both induced abortion OR 0.47 (0.25–0.90) and spontaneous abortion OR 0.31 (0.10–0.98). On the other hand, several studies have shown that some types of cancer are more common in patients with DM, particularly an association between T2DM and the risk of colorectal, pancreatic and BC. Moreover, it has been documented that 8–18 % of patients with a diagnosis of cancer have T2DM, and the average age is around 65 years old. It is very interesting that both diseases coexist, and that both share risk factors for their development, such as age, gender, obesity, diet, consumption of alcohol and smoking [47]. This risk is likely related to the tumorigenesis effect of insulin and its interaction with the similar growth factor receptors, as well as the use of different treatments, where metformin plays an important role in the avoidance of cancer development [48]. Epidemiologic studies indicate that moderate alcohol consumption increases BC risk in women [49]. In our study, T2DM and alcoholism were associated with an increased risk of developing BC.
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It is likely that the differences observed in the current and other studies may be due to several factors, principally with regard to the genetic background. However, other important factors include the selection criteria and the classification of samples according to BRCA1 and BRCA2 mutations. In conclusion, susceptibility to BC can be influenced by several factors, including genetic variants of DNA repair genes, abortion, breastfeeding, the use of contraceptives, family history of BC and other types of cancer, alcohol consumption, and T2DM. Acknowledgments Research supported by Universidad Auto´noma de Tamaulipas through grant UAT10-SAL-0306. Conflict of interest
There are no conflicts of interest.
Ethical Standard The study was approved by the institutional Ethics Committee, and written consent was obtained from each participant before enrolling into the study, together with a complete medical history.
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ORIGINAL ARTICLE
Polymorphisms of the XRCC1 gene and breast cancer risk in the Mexican population Nelly M. Macı´as-Go´mez • Valeria Peralta-Leal • Juan Pablo Meza-Espinoza • Melva Gutie´rrez-Angulo • Jorge Dura´n-Gonza´lez • Juan Manuel Ramı´rez-Gonza´lez Alejandra Gaspar-Del Toro • Adolfo Norberto-Rodrı´guez • Evelia Leal-Ugarte
•
Ó Springer Science+Business Media Dordrecht 2015
Abstract The purpose of this case–control study was to evaluate the association of XRCC1 Arg194Trp and Arg399Gln polymorphisms with susceptibility to breast cancer (BC) in a Mexican population. We analysed DNA samples from 345 BC patients and 352 control subjects by polymerase chain reaction-restriction fragment length polymorphism. The frequency of the 399Gln allele was 23 % in controls and 29 % in patients [OR 1.38 (1.08–1.76); p = 0.01]; genotypes in controls were 60, 36, and 4 % for Arg/Arg, Arg/Gln, and Gln/Gln, respectively, while in patients they were 53, 36, and 11 % [OR 2.71 (1.44–5.10); p = 0.0015 for the Gln/Gln genotype]. Regarding the Arg194Trp polymorphism, the frequency of Trp allele was 15 % in controls and 16 % in patients [OR 1.09 (0.82–1.46); p = 0.54]; the genotype frequencies in controls were 74, 23, and 3 % for Arg/Arg, Arg/Trp and
Trp/Trp, respectively, while in patients these were 73, 23, and 4 % [OR 1.41 (0.64–3.14); p = 0.39 for the Trp/Trp genotype]. Allele frequencies were consistent with Hardy– Weinberg equilibrium (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). Our results indicate that the 399Gln polymorphism is associated with an increased risk of BC. Additionally, we found that some covariates increase the risk of BC in Mexican women; namely, antecedent of abortions [OR 3.69 (2.17–6.27); p \ 0.001], not breastfeeding [OR 2.46 (1.45–4.18); p = 0.001], family history of BC [OR 15.9 (5.09–50.23); p \ 0.001], other type of family cancer [OR 31.5 (12.5–79.3); p \ 0.001], alcoholism [OR 17.7 (5.2–60.42); p \ 0.001], type 2 diabetes mellitus [OR 2.28 (1.26–4.10); p = 0.007], and contraceptive use [OR 2.28 (1.26–4.10); p \ 0.001]. Keywords Breast cancer XRCC1 gene Polymorphisms Risk factors
N. M. Macı´as-Go´mez A. Gaspar-Del Toro Departamento de Salud y Bienestar del Centro Universitario del Sur, Universidad de Guadalajara, Cd. Guzma´n, Jal., Mexico V. Peralta-Leal J. P. Meza-Espinoza J. Dura´n-Gonza´lez J. M. Ramı´rez-Gonza´lez E. Leal-Ugarte (&) Facultad de Medicina e Ingenierı´a en Sistemas Computacionales de Matamoros, Universidad Auto´noma de Tamaulipas, Sendero Nacional km 3, C. P. 87349 Matamoros, Tamaulipas, Mexico e-mail: [email protected]; [email protected] M. Gutie´rrez-Angulo Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitla´n de Morelos, Jal., Mexico J. Dura´n-Gonza´lez University of Texas at Brownsville, Brownsville, TX, USA A. Norberto-Rodrı´guez Hospital General ‘‘Alfredo Pumarejo’’, Matamoros, Tamps., Mexico
Introduction Breast cancer (BC) is the most common cause of cancer death and the most prevalent type of cancer in women, with a worldwide incidence of 13 % [1]. In Mexico, BC is considered the second cause of death in women [2]. BC is a multifactorial disease that results from complex interactions between genetic and environmental factors; however, it has been reported that hormonal factors like early age at menarche, late age at menopause, late age at first full term pregnancy, and hormone replacement therapy are the main risk factors for BC development [3]. It has also been suggested that polymorphisms in DNA repair genes may be involved in the aetiology of BC; among the candidates is the XRCC1 gene [4–7]. XRCC1 encodes a protein involved
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in DNA base excision repair (BER), which is 33 kb in length, contains 17 exons and is located at 19q13.2 [8]. More than 60 validated single nucleotide polymorphisms in the XRCC1 gene are listed in the Ensembl database [9]; however, only the non-synonymous polymorphisms rs1799782 (Arg194Trp; C194T) and rs25487 (Arg399Gln; G399A) have been shown to modify DNA repair capacity [10, 11]. The 194Trp variant has been associated with increased BER capacity, whereas the 399Gln variant has been related to a reduced repair capacity [11, 12]. The Arg194Trp polymorphism is located in the linker region separating the NH2-terminal domain from the central BRCT1 (BRCA1 C-terminus) domain. The linker region was also suggested as a potential binding domain of several interactive proteins, and the substitution of Arg to the hydrophobic Trp might affect its binding efficiency. The Arg399Gln polymorphism is located in the BRCT1 domain, which is essential for binding poly [ADP-ribose] polymerase 1. Cells carrying the BCRT1 mutation have been shown to be defective in responding to both X-ray and ultraviolet radiation [13]. Because the XRCC1 polymorphisms may alter DNA repair capacity, a number of studies have attempted to evaluate the impact of these polymorphisms with BC development; however, controversial results have been reported [4–6, 12, 14–31]. Here, we analysed whether there is any association of the XRCC1 polymorphisms Arg194Trp and Arg399Gln with BC in a Mexican population.
Materials and methods A total of 397 patients and 397 controls (cancer-free women) were enrolled; 345 patients and 352 controls had DNA available for genotyping. Patients were enrolled at the Oncology service of the Alfredo Pumarejo Hospital of the Secretary of Health in Matamoros, Tamaulipas Me´xico and from the Secretary of Health in Guzma´n City, Jalisco, along with women with BC who are part of RETO Guadalajara group (no governmental organisation). The mean age of the patients and controls was 47.2 and 50.7 years, respectively, and the average weight was 71 and 68.7 kg, respectively. DNA was extracted from peripheral blood of BC women and healthy women by CTAB–DTAB (denaturing cationic detergents, to precipitate DNA) and Miller (salting out the cellular proteins by dehydration and precipitation with a saturated NaCl solutions) methods. Alleles were detected by PCR–RFLP. The primers used were 50 -GCCCCGTCCCAG GTA-30 and 50 -AGCCCCAAGACCCTTTCACT-30 for Arg194Trp polymorphism, 50 -TTGTGCTTTCTCTGTGTCC A-30 and 50 -TCCTCCAGCCTTTTCTGATA-30 for Arg399Gln. PCR products were 491 and 615 bp,
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respectively. The restriction enzyme used for both polymorphisms was HpaII [32–35]. Allele and genotype frequencies were established by counting and the distribution of genotypes in both groups was compared by Chi square test. Hardy–Weinberg equilibrium (HWE) was evaluated by the Fisher exact test. Association was estimated by odds ratio (OR) and 95 % confidence interval (CI) in SPSS v10.0 software (the wild allele was taken as reference), p \ 0.05 was considered significant. Moreover, each allele and genotype was tested for association with BC risk factors, including BC family and other cancer types, body mass index (BMI), gynaecological and obstetric history, type 2 diabetes mellitus (T2DM), smoking, alcohol and coffee intake. Additionally, each of these variables was analysed between cases and controls to evaluate whether any of them increase the BC risk.
Results The genotype distribution and allele frequency of XRCC1 Arg194Trp and Arg399Gln polymorphisms in BC patients and controls are shown in Table 1. Allele frequencies in controls were consistent with HWE (p = 0.20 for Arg194Trp and p = 0.54 for Arg399Gln). A higher risk of BC was found for the Gln allele [OR 1.38 (1.08–1.76); p = 0.01] and for the Gln/Gln genotype [OR 2.71 (1.44–5.10); p = 0.0015]. However, there was no difference in distribution of the Arg194Trp polymorphism between BC patients and controls [OR 1.09 (0.82–1.46); p = 0.54]. Analysis performed to evaluate the association of variables with genotypes and BC development reported no association. However, in the variables analysis between cases and controls, we observed an increased risk in women who had undergone abortions, did not breastfeed, who had a family history of BC and other types of cancer, who consumed alcohol, used contraceptives, and had concomitant T2DM (Table 2). Age of onset of disease, menarche, menopause, BMI, coffee intake, and smoking showed no differences in this analysis.
Discussion In the present study, we analysed whether the XRCC1 Arg194Trp and Arg399Gln polymorphisms are associated with the risk of BC. Our findings suggest that the Arg399Gln polymorphism is related with an increased risk of BC in Mexican women. This finding agrees with most other similar studies. Dufloth et al. [25] revealed that the Arg399Gln polymorphism might be associated with an increased frequency of BC. Ali et al. [24] also reported that the
Breast cancer risk in the Mexican population Table 1 Genotype distribution and frequency of alleles of Arg194Trp and Arg399Gln polymorphisms of XRCC1 in patients with breast cancer and controls
Genotype/alleles Arg194Trp
Controls n = 352 (%)
Patients n = 345 (%)
Arg/Arg
259 (74)
250 (73)
1.0 (Reference)
Arg/Trp
82 (23)
80 (23)
1.01 (0.71–1.44)
0.95
Trp/Trp
11 (3)
15 (4)
1.41 (0.64–3.14)
0.39 0.74
Arg/Trp ? Trp/Trp
* Chi square test
OR (95 % CI)
p*
93 (26)
95 (28)
1.06 (0.76–1.48)
Arg
600 (85)
580 (84)
1.0 (Reference)
Trp
104 (15)
110 (16)
1.09 (0.82–1.46)
Genotype/alleles Arg399Gln
Controls n = 341 (%)
Patients n = 345 (%)
Arg/Arg
201 (60)
183 (53)
1.0 (Reference)
Arg/Gln
125 (36)
125 (36)
1.10 (0.80–1.51)
0.56
Gln/Gln
15 (4)
37 (11)
2.71 (1.44–5.10)
0.0015 0.12
OR (95 % CI)
Arg/Gln ? Gln/Gln
140 (41)
162 (47)
1.27 (0.94–1.72)
Arg
527 (77)
491 (71)
1.0 (Reference)
Gln
155 (23)
199 (29)
1.38 (1.08–1.76)
Table 2 Clinical variables of risk of breast cancer: logistic regression analysis Abortions
Controls n = 381 (%)
Patients n = 389 (%)
OR (95 % CI)
No
334 (87.7)
278 (71.5)
1.0 (Reference)
Yes
47 (12.3)
111 (28.5)
3.69 (2.17–6.27)
Breast-fed
n = 394 (%)
Yes
311 (78.9)
279 (70.3)
1.0 (Reference)
No
83 (21.1)
118 (29.7)
2.46 (1.45–4.18)
p*
0.001
n = 397 (%)
BC family
n = 397 (%)
n = 397 (%)
2 and 3 degree
392 (98.7)
329 (82.9)
1.0 (Reference)
1 degree
5 (1.3)
68 (17.1)
15.9 (5.09–50.23)
No
389 (98.0)
260 (65.5)
1.0 (Reference)
Yes
8 (2.0)
137 (34.5)
31.5 (12.5–79.3)
No
389 (98.0)
328 (82.6)
1.0 (Reference)
Yes T2DM
8 (2.0)
69 (17.4)
17.7 (5.2–60.42)
No
340 (85.6)
318 (80.1)
1.0 (Reference)
Yes
57 (14.4)
79 (19.9)
2.28 (1.26–4.10)
No
339 (85.4)
209 (52.6)
1.0 (Reference)
Yes
58 (14.6)
188 (47.4)
2.28 (1.26–4.10)
0.001
0.001
Other BC family 0.001
Alcoholism 0.001
0.007
Contraception 0.001
Gln allele was significantly more frequent in BC cases than in controls. Saadat et al. [4] reported that the Gln/Gln genotype significantly increased the risk of BC [OR 2.01
0.54 p*
0.01
(1.02–3.94); p = 0.041]. Likewise, Sterpone et al. [6] found association of Arg/Gln heterozygous and Gln/Gln homozygous with BC [OR 4.8 (1.56–14.78); p = 0.007, and OR 4.4 (1.13–17.1); p = 0.005, respectively]. Equally, Saadat et al. [5] conducted a meta-analysis with 43,716 subjects (20,837 patients and 22,879 controls) of different populations, such as Asian, European, American and Australian. They reported no association of XRCC1 genotypes with BC, but when the sample was stratified by ethnicity, the population from Asian countries with the Gln/Gln genotype had an increased BC risk. Recently, Wu et al. [29] performed a meta-analysis with 20,841 cases and 22,688 controls for Arg399Gln with three ethnic categories: Caucasian, Asian, and African; they concluded that the XRCC1 399Gln allele is a risk factor for BC development, especially among Asian (recessive model) and African (dominant model) populations [OR 1.54 (1.18–2.01) and OR 1.30 (1.07–1.60) respectively]. However, several studies showed no association between the 399Gln allele and BC risk when this allele was analysed without considering other covariates [14–16, 19–23, 26–28, 31]. In contrast, the Arg194Trp polymorphism did not show a significant association with BC in our analysis, in accordance with some studies [12, 15, 19, 22], but not with others; for example, Przybylowska-Sygut et al. [31] found a higher risk of BC for the Trp allele [OR 1.84 (1.16–2.95); p = 0.009] and for the Arg194Trp genotype [OR 1.91 (1.15–3.14); p = 0.011]. Likewise, Al et al. [30] reported association of 194Trp with BC [OR 4.26 (1.40–12.98); p = 0.006] and with the Arg/Trp genotype [OR 4.57 (1.47–14.21); p = 0.005]. On the other hand, we did not find any evidence that XRCC1 genotypes in combination with variables that could
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induce DNA damage or oxidative stress increase the BC risk; these variables include smoking, obesity, alcohol or coffee intake. However, in other studies, a major risk was observed when polymorphisms were combined with covariates [7, 16–19, 23, 36]. Instead, independent of genotype, we observed an increased BC risk in women who had undergone at least one abortion, who did not breastfeed, had a family history of BC and other types of cancer, consumed alcohol, used contraceptives, and had concomitant T2DM. Some studies have suggested that breastfeeding has a protective effect against BC [37–42], while others reported that it is unlikely to be protective [43, 44]. However, Thyagarajan et al. [20] reported no association between several variables and BC, including age at menarche, age at menopause, hormone replacement therapy, female history of cancer, age at first live birth, alcohol intake, smoking status, and waist-to-hip ratio. It has been well documented that hormonal factors are the most important factor involved in BC development, due to it being a hormonal tumour; in this sense, it is well known that pregnancy is a protective factor, and it has been estimated that every pregnancy reduces the risk of BC development by 7 % with respect to nulliparous women. Regarding abortion, it has been suggested that interrupted pregnancy is a risk factor because in the first weeks of pregnancy, the epithelial cells of mama experienced accelerated mitosis, but this is not followed by a differentiation stage; however, the results still are contradictory. In our study, we observed that having an abortion history is a risk factor for BC, but other studies have proposed that therapeutic abortion has a modest protective effect in patients with mutations in the BRCA2 gene [45]. Ilic et al. [46] reported that BC risk was reduced among women who had a history of any abortion OR 0.46 (0.24–0.88) the protective effect was found for both induced abortion OR 0.47 (0.25–0.90) and spontaneous abortion OR 0.31 (0.10–0.98). On the other hand, several studies have shown that some types of cancer are more common in patients with DM, particularly an association between T2DM and the risk of colorectal, pancreatic and BC. Moreover, it has been documented that 8–18 % of patients with a diagnosis of cancer have T2DM, and the average age is around 65 years old. It is very interesting that both diseases coexist, and that both share risk factors for their development, such as age, gender, obesity, diet, consumption of alcohol and smoking [47]. This risk is likely related to the tumorigenesis effect of insulin and its interaction with the similar growth factor receptors, as well as the use of different treatments, where metformin plays an important role in the avoidance of cancer development [48]. Epidemiologic studies indicate that moderate alcohol consumption increases BC risk in women [49]. In our study, T2DM and alcoholism were associated with an increased risk of developing BC.
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It is likely that the differences observed in the current and other studies may be due to several factors, principally with regard to the genetic background. However, other important factors include the selection criteria and the classification of samples according to BRCA1 and BRCA2 mutations. In conclusion, susceptibility to BC can be influenced by several factors, including genetic variants of DNA repair genes, abortion, breastfeeding, the use of contraceptives, family history of BC and other types of cancer, alcohol consumption, and T2DM. Acknowledgments Research supported by Universidad Auto´noma de Tamaulipas through grant UAT10-SAL-0306. Conflict of interest
There are no conflicts of interest.
Ethical Standard The study was approved by the institutional Ethics Committee, and written consent was obtained from each participant before enrolling into the study, together with a complete medical history.
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