Association of Genetic Variations in XRCC1 and ERCC1 Genes with Sporadic Breast Cancer

authors:

avatar Saeid Ghorbian ORCID 1 , * , avatar Mansooreh Nargesian 2 , avatar Sasan Talaneh 1 , avatar Omid Asnaashari 3 , avatar Rasol Sharifi 4

Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar, Iran
Young Researchers and Elite Club, Ahar Branch, Islamic Azad University, Ahar, Iran
Department of Radiation Oncology, Omid Hospital, Western Azerbaijan University of Medical Sciences, Urmia, Iran
Department of Biology, Ahar Branch, Islamic Azad University, Ahar, Iran

how to cite: Ghorbian S, Nargesian M , Talaneh S, Asnaashari O, Sharifi R. Association of Genetic Variations in XRCC1 and ERCC1 Genes with Sporadic Breast Cancer. Gene Cell Tissue. 2018;5(2):e80166. https://doi.org/10.5812/gct.80166.

Abstract

Background:

Recently, findings have validated the significant role of DNA damage genes related to the pathogenesis of breast cancer (BC). The aim of the present investigation was to evaluate possibility roles of two common XRCC1 (rs25487; A > G) and ERCC1 (rs3212964; A > G) gene polymorphisms with the risk of sporadic BC.

Methods:

In a case-control study, consisting of 100 females identified with sporadic BC and 100 malignancy-free females as the control group. We used Tetra-ARMS Polymerase Chain Reaction (PCR) and PCR-Restriction Fragment Length Polymorphism (RFLP) methods to determine genotype frequencies of XRCC1 and ERCC1 genes.

Results:

The findings did not reveal a statistically significant difference in the genotype frequencies of XRCC1 and ERCC1 genes between the two groups (P > 0.05). The frequency of G mutant allele for XRCC1 and ERCC genes was higher in cases compared to controls, while the difference between the groups was not statistically significant (P = 0.202; OR: 1.312; CI: 0864 - 1.994), (P = 0.352; OR: 1.213; CI: 0.808 - 1.820).

Conclusions:

The current results provide evidence against the hypothesis that XRCC1 (rs25487) and ERCC1 (rs3212964) gene polymorphisms may be associated with a predisposition to sporadic BC.

1. Background

Breast cancer (BC) is the most prevalent type of malignancy in females, with two patterns, including hereditary and sporadic (1). The environmental risk factors, consist of ionizing radiation (IR), carcinogenic components, heterocyclic aromatic amines, alcohol consumption, and free radicals (2, 3). Genetic factors are compound conditions of BC (4). During DNA damage, eukaryotic cells use appropriate processes to repair multiple forms of DNA damages to protect genome stability and integrity. Repairing pathways have significant roles in maintaining genomic integrity in comparison with carcinogenic components and mutagens (5). During exposure of DNA to IR, the double-stranded DNA may be broken and this increases the risk of BC progress (6). In humans, base excision repair (BER) and Nucleotide Excision Repair (NER) comprised of the two most common DNA repair mechanisms (7, 8). In BER systems, there are eleven DNA damage special proteins that contribute to a specific function. Among these components, X-ray repair cross-complementing group 1 (XRCC1) participates in the BER system (9, 10). Another significant molecule, excision repair cross-complementation 1 (ERCC1), which encodes an ERCC1 protein, is involved in the NER pathway, eliminating significant DNA damage generated through environmental agents including toxic compounds or ultraviolet (10). Genetic variations, such as single nucleotide polymorphism (SNP) may exchange amino acids or modify DNA conformations, which is related to cancer risk or human disorders (11, 12). Single nucleotide polymorphism molecular analysis could facilitate prognosis, diagnosis, and remedy of human disorders (13). With the crucial roles of DNA repairing machinery components in human genome integrity, it is possible to reveal significant appearances of nucleotide changes in the DNA repair genes and the risk of malignancies (14). Preliminary investigations have shown several SNPs in the XRCC1 and ERCC1 genes involved in tumorigenesis. According to previous considerations, findings have revealed contradictory results regarding several diseases and different ethnic geographical regions (15-17). To provide greater insight regarding the association between particular SNPs in the XRCC1 and ERCC1 genes in the tumorigenesis of BC, this study aimed at evaluating the associated between XRCC1 (rs25487) and ERCC1 (rs3212964) gene polymorphisms and the risk of sporadic BC in females of the northwestern of Iran.

2. Methods

2.1. Patients and Controls

In a case-control investigation, we recruited 100 females, who had been referred to the Omid hospital of Urmia, Iran. All cases were diagnosed as having histologically sporadic BC (mean age 44.69 ± 5.12 years), and 100 age-matched healthy females (mean age 44.5 ± 6.5 years), who attended the related hospital for conventional physical assessment, were registered as the control group, during June 2015 to April 2017. All individuals were from the same geographic province. The clinical features of each participant, including history of smoking, drinking, BRCA1/BRCA2 gene mutation status, and other malignancy history, was collected through a survey and signed informed consents were obtained from all participants. Exclusion criteria comprised of having metastasized carcinoma or identified mutations in the BRCA1/BRCA2 genes, and having received a radiotherapy or chemotherapy regimen. This study excluded all samples, which did not have the criteria of the community before genetic variant analysis. The ethical review board of Omid hospital of Urmia approved the investigation.

2.2. Genetic Variant Analysis

We selected two common SNPs in XRCC1 (rs25487) and ERCC1 (rs3212964) genes to evaluate the genetic susceptibility of sporadic BC. The genomic DNA was collected from white blood cells using the salting-out method reported by Miller et al. (18). For quantitive and qualitative appraisal of extracted DNA, NanoDrop I (Thermo Scientific Fisher, USA) and 1% agarose gel electrophoresis were used, respectively.

For determining the genotype frequencies, we used Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and ARMS-PCR (Amplification-refractory mutation system) techniques. The primer sequence of rs25487 was (F): 5’-TTGTGCTTTCTCTGTGTCCA-3’, (R) 5’-TCCTCCAGCCTTTTCTGATA-3’ and digested PCR products were obtained using Restriction Enzyme MSP I (Thermo Scientific Fisher, USA), according to the company protocols and separated on 2% agarose gel. For the amplification of the rs3212964 region, Tetra primer sequences were used, including; (Forward Inner): 5’-TCACATCCTCTCTCCCGTAGGGATCA-3’, (Reverse Inner):5’-GGGAAAGAGGGCTTGAGGAATTATAAGTC-3’, (Forward Outer): 5’-GTGACCTCCAACCTCTACCCAGTTCTC-3’, (Reverse Outer): 5’-ACATTAGAGCTGAGACCCAAAGGAGGAT-3’. The polymorphic region extended through PCR Thermal Cycler (Eppendorf, Germany) in a 25-µL final volume, comprised of 50 ng of genomic DNA, 12.5 µL of 2X Master Mix Red (Ampliqon, Denmark), and each of the primers at a final concentration of 10 pmole. Annealing temperatures were as follows: rs25487 at 58°C and rs3212964 at 60°C. During PCR products digestion, rs25487 (G: 375 + 240 bp, A: 615 bp) and rs3212964 (A allele: 161 bp, G allele: 119 bp, two outer primers: 225 bp (gene control) fragments were generated. To confirm genotype frequencies, 15% of specimens were chosen for double assessment. Additionally, 10% of random individuals with the two SNPs were verified by direct sequencing.

2.3. Statistical Analysis

Relationships between the two SNPs and sporadic breast cancer risk was evaluated by chi-square test, odds ratios (ORs) and their 95% confidence intervals (CIs), which were calculated using the logistic regression model. Statistical analysis was performed using the SPSS software version 22.0 (SPSS Inc., Chicago, IL, USA). P values of < 0.05 were considered as statistically significant.

3. Results

The genotype frequencies of the two SNPs are shown in Table 1. The current findings did not reveal statistically significant differences between case and control groups (P = 0.364). In order to assess whether an association was present between gene polymorphism and the risk of sporadic BC in codominant, dominant, and recessive genetic models, the genotype frequencies of each group was consolidated in new heredity models, then, odds ratios and 95% CI were calculated. The AG/AA+GG genotypes did not demonstrate a risk of sporadic BC (P = 0.254; OR:1.385; CI:0.791 - 2.425; Table 1).

In addition, AA/AG+GG and GG/AA+AG genotype models of the XRCC1 gene did not show a significantly increased risk of sporadic BC (P > 0.05; Table 1).

Of the 100 patients studied for the XRCC1 gene polymorphism, the frequency of the G mutant allele did not show a statistically significant difference between the two groups (P = 0.202; OR: 1.312; CI: 0864 - 1.994; Table 1).

Table 1.

Comparative Genotype Frequencies of XRCC1 and ERCC1 Gene Polymorphisms Between Groups

Gene PolymorphismCase Group (n = 100)aControl Group (n = 100)aTotal (n = 200)ORCI 95%P Value
UpDown
XRCC1 (rs25487; A>G)
Codominant1.3852.4250.7910.254
AG48 (55)40 (45)88
AA+GG52 (46)60 (54)112
Dominant1.5002.6260.8570.155
AA40 (44)50 (56)90
AG+GG60 (55)50 (45)110
Recessive1.2272.9860.5040.651
GG12 (55)10 (45)22
AG+AA88 (49)90 (51)178
Frequency1.3121.9940.8640.202
Frequency of G allele72 (55)60 (45)132
Frequency of A allele128 (48)140 (52)268
ERCC1 (rs3212964; A > G)
Codominant1.0421.8250.5950.886
AG43 (51)42 (49)85
AA+GG57 (50)58 (50)115
Dominant0.8141.4290.4630.473
AA39 (47)44 (53)83
AG+GG61 (52)56 (48)117
Recessive1.3482.8870.6300.440
GG18 (56)14 (44)32
AG+AA82 (49)86 (51)168
Frequency1.2131.8200.8080.352
Frequency of G allele79 (53)70 (47)149
Frequency of A allele121 (48)130 (52)251

In the current investigation, a statistically significant difference was not shown in genotype frequencies of the ERCC1 gene between sporadic BC patients compared to controls (P = 0.666). Similar to the XRCC1 gene polymorphism analysis, the genotype frequencies of the ERCC1 gene were assessed for three heredity models. The AG/AA+GG genotypes did not increase the risk of sporadic BC (P = 0.886; OR: 1.042; CI: 0.595 - 1.825; Table 1).

In addition, AA/AG+GG and GG/AA+AG heredity models of ERCC1 gene did not show a significantly increased risk of sporadic BC (P > 0.05), Table 1. Also, the frequency of the G mutant allele was higher in the case group (n = 79) compared to the controls (n = 70), while the difference between groups was not statistically significant (P = 0.352; OR: 1.213; CI: 0.808-1.820; Table 1).

Gel electrophoresis of the PCR-RFLP products from of XRCC1 (rs25487) gene on 2% agarose gel electrophoresis. Lanes 1 and 2: GG genotype (375 bp, 240 bp); Lane 3: AA genotype (615 bp); Lanes 4: AG genotype (615 bp, 375, 240); M: DNA size marker 100 bp.
Gel electrophoresis of the PCR-RFLP products from of XRCC1 (rs25487) gene on 2% agarose gel electrophoresis. Lanes 1 and 2: GG genotype (375 bp, 240 bp); Lane 3: AA genotype (615 bp); Lanes 4: AG genotype (615 bp, 375, 240); M: DNA size marker 100 bp.
Gel electrophoresis of the PCR-RFLP products from of ERCC1 ( rs3212964) gene on 2% agarose gel electrophoresis. Lane 1: AA genotype (225 bp, 161 bp); Lanes 2 and 4: AG genotype (225 bp, 161 bp, 119 bp); Lane 3: GG genotype (119 bp; 225 bp); M: DNA size marker 100 bp.
Gel electrophoresis of the PCR-RFLP products from of ERCC1 ( rs3212964) gene on 2% agarose gel electrophoresis. Lane 1: AA genotype (225 bp, 161 bp); Lanes 2 and 4: AG genotype (225 bp, 161 bp, 119 bp); Lane 3: GG genotype (119 bp; 225 bp); M: DNA size marker 100 bp.

4. Discussion

The current investigation studied the association of two SNPs in the XRCC1 and ERCC1 genes with the risk of sporadic BC in females of northwestern Iran.

The findings revealed that the XRCC1 (rs25487) and ERCC1 (rs3212964) gene polymorphisms were not associated with an enhanced chance of sporadic BC. The present investigation is the beginning of a case-control survey to evaluate the association between two nucleotide changes in the BER pathway related-genes and the risk of sporadic BC in Iranian females.

During the DNA base pair repair procedure, the XRCC1 gene was implicated in the change of DNA damages and single-strand DNA disputes through DNA ligase III enzyme, at its carboxyl and DNA polymerase beta and poly ADP-Ribose polymerase at the site of the damaged DNA (15, 19). The XRCC1 function is needed for DNA repair and genome integrity (20). DNA repairing deficiency may lead to accumulated DNA damages and mutations, which thereafter beginning conditions such as malignancies (21). The XRCC1 gene polymorphism is found inside the XRCC1 BRCA1 carboxyl-terminal domain (BRCT I) and may be modified for protein construction and function. Previous investigations have reported that the genetic variants of the XRCC1 (rs25487) gene are associated with the risk of BC (22, 23). Of note, the documents are not compatible with the current investigation of Iranian females in the Western Azerbaijan province. Zhu et al. proposed that the XRCC1 (rs25487) gene polymorphism may increase the risk of BC (15). In addition, Luo et al. revealed that the G allele in XRCC1 increased the risk of BC and may contribute to tumorigenesis in Chinese females (24). Although epidemiological investigations of the XRCC1 gene polymorphism with the risk of BC have been assessed in various populations, the findings are contradictory and ambiguous. Similar to the current findings, Al Mutairiet al.’s study did not reveal a positive association between XRCC1 (rs25487) gene polymorphism with the risk of BC in Saudi females (25). Ding et al.’s study on Chinese females showed an increased risk of XRCC1 (rs25487) gene polymorphism with BC (26), which is in contrast with the current findings, and a meta-analysis published by Wu et al. on 44 case-control investigations (27). Taken together, the current results did not suggest that the XRCC1 gene polymorphism plays a significant role in the initiation of BC.

Similar to the current findings, previous investigations did not show an association between the ERCC1 (rs3212964) gene polymorphism and the risk of BC (15, 28). Furthermore, ASE-1 has been found in an antisense orientation and overlaps with the ERCC1 gene and is likely involved with RNA polymerase I transcription complex. Aiub et al. showed the BER mechanism was implicated in DNA damages repair, as a result of compounds such as N-nitrosodiethylamine (29). However, preliminary studies did not reveal a significant association between nucleotide change in the ERCC1 gene and the risk BC.

The contradictory results may be due to the low demographic power, inadequate sample size, different allele frequencies, differences in the genetic background of the population (ethnic and racial). In addition, another possibility may be social behavior and environmental factors affecting the risk of BC. However, more investigations are needed to evaluate the role of genetic variations of BER mechanism genes in the pathogenesis of BC. The current results provided evidence that XRCC1 (rs25487) and ERCC1 (rs3212964) gene polymorphisms may implement both independent and interactive impacts on the progress of breast cancer. While BC is considered as a heterogeneous disease, large-designed geographic investigations endeavoring to consider gene-gene and gene-environment interactions are needed for the future studies.

Acknowledgements

References

  • 1.

    Shu XO, Cai Q, Gao YT, Wen W, Jin F, Zheng W. A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2003;12(12):1462-7. [PubMed ID: 14693738].

  • 2.

    Maas P, Barrdahl M, Joshi AD, Auer PL, Gaudet MM, Milne RL, et al. Breast cancer risk from modifiable and nonmodifiable risk factors among white women in the United States. JAMA Oncol. 2016;2(10):1295-302. [PubMed ID: 27228256]. [PubMed Central ID: PMC5719876]. https://doi.org/10.1001/jamaoncol.2016.1025.

  • 3.

    Kotepui M. Diet and risk of breast cancer. Contemp Oncol (Pozn). 2016;20(1):13-9. [PubMed ID: 27095934]. [PubMed Central ID: PMC4829739]. https://doi.org/10.5114/wo.2014.40560.

  • 4.

    Xu F, Li D, Zhang Q, Fu Z, Yuan W, Pang D, et al. Association of CD27 and CD70 gene polymorphisms with risk of sporadic breast cancer in Chinese women in Heilongjiang Province. Breast Cancer Res Treat. 2012;133(3):1105-13. [PubMed ID: 22399187]. https://doi.org/10.1007/s10549-012-1987-7.

  • 5.

    Dizdaroglu M. Oxidatively induced DNA damage and its repair in cancer. Mutat Res Rev Mutat Res. 2015;763:212-45. [PubMed ID: 25795122]. https://doi.org/10.1016/j.mrrev.2014.11.002.

  • 6.

    Kamali M, Hamadani S, Neamatzadeh H, Mazaheri M, Zare Shehneh M, Modaress Gilani M, et al. Association of XRCC2 rs3218536 polymorphism with susceptibility of breast and ovarian cancer: A systematic review and meta-analysis. Asian Pac J Cancer Prev. 2017;18(7):1743-9. [PubMed ID: 28749098]. [PubMed Central ID: PMC5648374]. https://doi.org/10.22034/APJCP.2017.18.7.1743.

  • 7.

    Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15(7):465-81. [PubMed ID: 24954209]. https://doi.org/10.1038/nrm3822.

  • 8.

    Drohat AC, Coey CT. Role of Base Excision "Repair" Enzymes in erasing epigenetic marks from DNA. Chem Rev. 2016;116(20):12711-29. [PubMed ID: 27501078]. [PubMed Central ID: PMC5299066]. https://doi.org/10.1021/acs.chemrev.6b00191.

  • 9.

    Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13(7):411-24. [PubMed ID: 22713970]. https://doi.org/10.1038/nrm3376.

  • 10.

    Karahalil B, Bohr VA, Wilson D3. Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk. Hum Exp Toxicol. 2012;31(10):981-1005. [PubMed ID: 23023028]. [PubMed Central ID: PMC4586256]. https://doi.org/10.1177/0960327112444476.

  • 11.

    Lu L, Katsaros D, Mayne ST, Risch HA, Benedetto C, Canuto EM, et al. Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer. Carcinogenesis. 2012;33(11):2119-25. [PubMed ID: 22822098]. https://doi.org/10.1093/carcin/bgs243.

  • 12.

    Lu L, Risch E, Deng Q, Biglia N, Picardo E, Katsaros D, et al. An insulin-like growth factor-II intronic variant affects local DNA conformation and ovarian cancer survival. Carcinogenesis. 2013;34(9):2024-30. [PubMed ID: 23677070]. https://doi.org/10.1093/carcin/bgt168.

  • 13.

    McLeod HL. Cancer pharmacogenomics: early promise, but concerted effort needed. Science. 2013;339(6127):1563-6. [PubMed ID: 23539596]. [PubMed Central ID: PMC3900028]. https://doi.org/10.1126/science.1234139.

  • 14.

    Ozgoz A, Hekimler Ozturk K, Yukselturk A, Samli H, Baskan Z, Mutlu Icduygu F, et al. Genetic Variations of DNA Repair Genes in Breast Cancer. Pathol Oncol Res. 2017. [PubMed ID: 28983784]. https://doi.org/10.1007/s12253-017-0322-3.

  • 15.

    Zhu G, Wang L, Guo H, Lu L, Yang S, Wang T, et al. DNA repair genes XRCC1 and ERCC1 polymorphisms and the risk of sporadic breast cancer in Han women in the Gansu Province of China. Genet Test Mol Biomarkers. 2015;19(7):387-93. [PubMed ID: 25961110]. https://doi.org/10.1089/gtmb.2015.0001.

  • 16.

    Zheng LR, Wang XF, Zhou DX, Zhang J, Huo YW, Tian H. Association between XRCC1 single-nucleotide polymorphisms and infertility with idiopathic azoospermia in northern Chinese Han males. Reprod Biomed Online. 2012;25(4):402-7. [PubMed ID: 22868082]. https://doi.org/10.1016/j.rbmo.2012.06.014.

  • 17.

    Wang Q, Tan HS, Zhang F, Sun Y, Feng NN, Zhou LF, et al. Polymorphisms in BER and NER pathway genes: effects on micronucleus frequencies among vinyl chloride-exposed workers in Northern China. Mutat Res. 2013;754(1-2):7-14. [PubMed ID: 23562908]. https://doi.org/10.1016/j.mrgentox.2013.03.007.

  • 18.

    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215. [PubMed ID: 3344216]. [PubMed Central ID: PMC334765].

  • 19.

    Hanssen-Bauer A, Solvang-Garten K, Akbari M, Otterlei M. X-ray repair cross complementing protein 1 in base excision repair. Int J Mol Sci. 2012;13(12):17210-29. [PubMed ID: 23247283]. [PubMed Central ID: PMC3546746]. https://doi.org/10.3390/ijms131217210.

  • 20.

    de Sousa MML, Bjoras KO, Hanssen-Bauer A, Solvang-Garten K, Otterlei M. p38 MAPK signaling and phosphorylations in the BRCT1 domain regulate XRCC1 recruitment to sites of DNA damage. Sci Rep. 2017;7(1):6322. [PubMed ID: 28740101]. [PubMed Central ID: PMC5524842]. https://doi.org/10.1038/s41598-017-06770-3.

  • 21.

    Rowe BP, Glazer PM. Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms. Breast Cancer Res. 2010;12(2):203. [PubMed ID: 20459590]. [PubMed Central ID: PMC2879573]. https://doi.org/10.1186/bcr2566.

  • 22.

    Mitra AK, Singh N, Singh A, Garg VK, Agarwal A, Sharma M, et al. Association of polymorphisms in base excision repair genes with the risk of breast cancer: a case-control study in North Indian women. Oncol Res. 2008;17(3):127-35. [PubMed ID: 18669164].

  • 23.

    Roberts MR, Shields PG, Ambrosone CB, Nie J, Marian C, Krishnan SS, et al. Single-nucleotide polymorphisms in DNA repair genes and association with breast cancer risk in the web study. Carcinogenesis. 2011;32(8):1223-30. [PubMed ID: 21622940]. [PubMed Central ID: PMC3149207]. https://doi.org/10.1093/carcin/bgr096.

  • 24.

    Luo H, Li Z, Qing Y, Zhang SH, Peng Y, Li Q, et al. Single nucleotide polymorphisms of DNA base-excision repair genes (APE1, OGG1 and XRCC1) associated with breast cancer risk in a Chinese population. Asian Pac J Cancer Prev. 2014;15(3):1133-40. [PubMed ID: 24606430].

  • 25.

    Al Mutairi FM, Alanazi M, Shalaby M, Alabdulkarim HA, Pathan AA, Parine NR. Association of XRCC1 gene polymorphisms with breast cancer susceptibility in Saudi patients. Asian Pac J Cancer Prev. 2013;14(6):3809-13. [PubMed ID: 23886187].

  • 26.

    Ding P, Yang Y, Cheng L, Zhang X, Cheng L, Li C, et al. The relationship between seven common polymorphisms from five DNA repair genes and the risk for breast cancer in northern Chinese women. PLoS One. 2014;9(3). e92083. [PubMed ID: 24642895]. [PubMed Central ID: PMC3958445]. https://doi.org/10.1371/journal.pone.0092083.

  • 27.

    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(9):2237-43. [PubMed ID: 22296363].

  • 28.

    Han W, Kim KY, Yang SJ, Noh DY, Kang D, Kwack K. SNP-SNP interactions between DNA repair genes were associated with breast cancer risk in a Korean population. Cancer. 2012;118(3):594-602. [PubMed ID: 21751184]. https://doi.org/10.1002/cncr.26220.

  • 29.

    Aiub CA, Mazzei JL, Pinto LF, Felzenszwalb I. Participation of BER and NER pathways in the repair of DNA lesions induced at low N-nitrosodiethylamine concentrations. Toxicol Lett. 2004;154(1-2):133-42. [PubMed ID: 15475187]. https://doi.org/10.1016/j.toxlet.2004.07.012.