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Abstract

X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case–control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case–control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes.

Keywords

breast cancer polymorphism antigen hypoxia meta-analysis ethnicity reproductive factors food habits

Introduction

X-ray repair cross complementary group (XRCC) gene is one of the most studied candidate gene involved in different types of cancers.^{1

–4} XRCC genes are involved in base excision repair (BER) and single-strand break in damaged DNA in human genome.^{1

–5} Molecular epidemiological studies have shown that XRCC genes are significantly associated with lung cancer,^{6

–9} oral cancer,¹⁰ bladder cancer,^{11
–13} ovarian cancer,^14,15 esophageal cancer,¹⁶ and gastric cancer.^{17

–23} Moreover, studies have revealed that XRCC gene polymorphism is highly variable in different ethnic populations.^{24

–28}

Studies have shown that defect in DNA repair mechanism is significantly associated with the increased risk of breast cancer (BC) in females.²⁹ Molecular epidemiological studies have been carried out globally to investigate the association of DNA repair mechanism genes with the risk of BC in females from different ethnicity.³⁰ Studies have revealed that polymorphisms in XRCC1A (Arg194Trp) and XRCC 3 (Thr241Met) genes are significantly associated with the increased risk of BC in different ethnic populations, though the results are inconsistent which may be due to environmental factors, ethnocultural variations, and/or variations in linkage disequilibrium of these 2 genes, namely, XRCC1A and XRCC3.^{24,29,31

–41}

In India, BC is an emerging public health concern.⁴² Thus, identification of epidemiological and genetic factors significantly associated with the increased or decreased risk of BC in females from different ethnic groups of India is at utmost need to combat this disease at the earliest.⁴³ In recent years, Population Based Cancer Registry (PBCR) data of India have reported high number of BC cases in females from northeast (NE) region of India.^43,44 The PBCR data have shown incidence of BC in females of NE region varies from 7.2 per 100 000 populations in Tripura to 30 per 100 000 populations in Aizawl and Kamrup districts.⁴³ Molecular epidemiological studies have revealed that mutations and/or polymorphisms in tumor suppressor genes, DNA repair mechanism genes, and innate immune pathway genes are significantly associated with the increased risk of BC in females from NE region of India.^45,46 Our earlier study has found that 22-base pair deletion in promoter region of TLR2 gene significantly increased the risk of BC in females from NE region of India carrying proline allele at codon 72 of their TP53 gene.⁴⁷ Thus, to elucidate the association of DNA repair mechanism genes with the risk of BC in females from this region, the present case–control study was carried out in 4 different states of NE region, India, namely, Assam, Meghalaya, Tripura, and Mizoram. The present molecular epidemiological study was aimed to investigate the association of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) polymorphism with the risk of BC in females from NE region which may be beneficial for prognostic purposes.

Materials and Methods

Ethics Statement

This study has been approved by the institutional ethics committee of Regional Medical Research Centre, Indian Council of Medical Research–NE Region, Dibrugarh, Assam (RMRC/Dib/IEC(Human)/2008-09/3243 dated February 19, 2009). All the participants, both cases and controls, provided their written informed consent to be included in this study.

Study Participants and Specimen Collection

This case–control study, conducted from 2010 to 2014, included females from 4 states of NE region of India, namely, Assam, Meghalaya, Mizoram, and Tripura. All 464 BC cases were confirmed by histopathological analysis and all were newly diagnosed. Patients with severe clinical symptoms, patients with recurrent cancer, patients too old to be interviewed, and patients refused to be interviewed were excluded from this study. Five hundred thirty-four neighborhood controls, that is, apparently healthy female participants, were selected by organizing community surveys from the neighborhood of cases. Exclusion criteria for selecting controls were females not willing to participate in the study or having any other type of disease or have undergone blood transfusion in the last 1 year. Information on sociodemographic factors, anthropogenic measurements, and other putative risk factors was collected from the cases and controls by face-to-face interviews, and information gathered was recorded in a predesigned questionnaire. Peripheral whole blood was collected from each study participant in EDTA-containing vials and stored at −80C until analyzed. Breast tissue biopsy samples were immediately fixed in neutral-buffered formalin and kept for 48 hours. Subsequently, the fixed breast tissue samples were thoroughly washed in 70% ethanol, dehydrated in graded series of ethanol, cleaned in xylene, and embedded in paraplast (Sigma St. Louis, MO, USA) for further histological and immunohistochemical analyses.

Genotyping of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) Polymorphisms

Isolation of DNA for genotyping was carried out by using Qiagen DNeasy(R) Blood kit, and amplification and identification of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) genes were performed using the following primer sequences: 5′-GCC CCG TCC CAG GTA-3′ (forward), 5′-AGC CCC AAG ACC CTT CAC T-3′ (reverse) for XRCC1A (Arg194Trp) and 5′-GGT CGA GTG ACA GTC CAA AC-3′ (forward), and 5′-TGC AAC GGC TGA GGG TCT T-3′ (reverse) for XRCC3 (Thr241Met) gene, respectively. Genotyping of XRCC1A and XRCC3 was carried out by polymerase chain reaction–based restriction fragment length polymorphism (PCR-RFLP) as described by Zhang et al.⁴⁸ In brief, PCR was performed with 100 ng of genomic DNA using 12.50 µL GoTaq Hot Start master mix (2x; Promega, Madison, WI, USA) with 9.0 µL nuclease-free water (Promega), 0.50 µL 25 mmol/L magnesium chloride (Promega), and 10 pmol 0.5 µL of each forward and reverse primers. Polymerase chain reaction was carried out using GeneAmp PCR system 9700 (Applied Biosystem, USA). The PCR conditions were initial denaturation at 95°C for 2 minutes followed by 32 cycles at 95°C for 0.5 seconds, 63°C for 0.5 seconds, and 72°C for 60 seconds for XRCC1A (Arg194Trp) and 95°C for 0.5 seconds, 65°C for 0.5 seconds, and 72°C for 60 seconds for XRCC3 (Thr241Met) gene followed by at 72°C for 10 minutes for both the primers. The amplified products were subjected to MspI (New England Biolabs, Beverly, Massachusetts) and NlaIII (New England Biolabs) restriction enzyme digestion for XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) genes, respectively, in a 7.50 µL reaction mixture containing restriction endonuclease and reaction buffer following the manufacturer’s protocol. The reaction mixture was incubated at 37°C for 16 hours. The restriction-digested products were then resolved on polyacrylamide gel electrophoresis for XRCC1A (Arg194Trp) and on 3% agarose gel for XRCC3 (Thr241Met) genotyping, respectively. Gels were stained with ethidium bromide and visualized in ultraviolet light. The PCR-RFLP products were further confirmed by Lab Chip (Caliper Life Sciences Inc, Waltham, Massachusetts).

Statistical Analysis

Univariate and multivariate logistic regression analyses were performed by using SPSS version 17.0 (SPSS Inc, Chicago, Illinois). A P value <.05 was taken as statistically significant. Initially, we carried out univariate logistic regression analysis where a single putative risk factor was analyzed to determine the crude odds ratio (OR) and 95% confidence interval (CI). The multiple logistic regression analysis was performed adjusted for age, region, menstrual status, marital status, betel nut chewing, tobacco smoking or chewing, alcohol consumption, dry fish and dry meat, and bamboo shoots consumption. We also carried out stratified analysis where the study population was stratified into 2 groups, based on their menopausal status: group 1 participants were premenopausal females, whereas group 2 consisted of postmenopausal females from NE region of India. Before performing association study, the Hardy-Weinberg equilibrium (HWE) for any deviation from expected allele frequencies was tested by using χ2 test.

Results

Patient Characteristics

The study comprised of 464 histopathologically confirmed newly diagnosed BC cases and 534 apparently healthy neighborhood community control samples collected from adjacent regions from where cases were obtained. Demographic features of both cases and controls are presented in Table 1.

Table 1.

Demographic Features of Study Population.

S. No.	Demographic Features	Cases With Breast Cancer	Apparently Healthy Controls
1	Mean age (SD)	47.31 (10.96), n = 454	41.89 (11.02), n = 484
2	Menstrual status	n = 454	n = 484
	Premenopausal	237	366
	Postmenopausal	217	118
3	Marital status	n = 459	n = 518
	Married	430	471
	Unmarried	29	47
4	Family history of BC	n = 464	n = 534
	Yes	7	8
	No	457	526

Abbreviations: BC, breast cancer; SD, standard deviation.

Test for HWE

Before carrying out association studies with genotypic data, control results were tested for HWE. Both XRCC1A (Arg194Tryp) and XRCC3 (Thr241Met) polymorphisms in control samples did not deviate from HWE (P = .114 for XRCC1A [Arg194Trp] gene and P = .250 for XRCC3 [Thr241Met] gene).

Association of XRCC1A (Arg194Trp) Polymorphisms With the Risk of BC in Females From NE Region of India

To investigate the association of XRCC1A (Arg194Tryp) polymorphism with the increased risks of BC, both univariate and multivariate logistic regression analyses were carried out. Multivariate logistic regression analysis was performed after adjustment of age, region, menstrual status, marital status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit. Univariate logistic regression analysis has revealed that tryptophan allele (R/W-W/W genotype) in XRCC1A (Arg194Trp) gene significantly increased the risk of BC in females from NE region of India (crude OR = 1.31, 95% CI = 1.02-1.70, P < .05; Table 2), whereas multivariate logistic regression analysis after adjustment of age, region, menstrual status, marital status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit has revealed that tryptophan allele in XRCC1A genotype increased the risk of BC 1.44-fold (adjusted OR = 1.44, 95% CI = 1.06-1.97, P < .05 for R/W-W/W genotype; Table 2).

Table 2.

Association of XRCC1A (Arg194Trp) Polymorphism With the Risk of Breast Cancer in Females From NE Region of India.

Genotypes	Cases	Controls	Crude OR (95% CI)	P Value	AOR (95% CI)	P Value
Codominant model	n = 464	n = 534
R/R	263	338	Ref		Ref
R/W	178	166	1.37 (1.05-1.79)	.018^a	1.42 (1.03-1.95)	.031^a
W/W	23	30	0.98 (0.55 -1.73)	.959	1.69 (0.82-3.46)	.152
Dominant model	n = 464	n = 534
R/R	263	338	Ref		Ref
R/W-W/W	201	196	1.31 (1.02-1.70)	.033^a	1.44 (1.06-1.97)	.019^a
Recessive model	n = 464	n = 534
R/R-R/W	441	504	Ref		Ref
W/W	23	30	0.87 (0.50 -1.53)	.642	1.45 (0.72-2.95)	.294

Abbreviations: AOR, adjusted OR, adjusted for age, region, marital status, menopausal status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit; CI, confidence interval; NE, northeast; OR, odds ratio; R, arginine; W, tryptophan; XRCC, X-ray repair cross complementary.

^aStatistically significant at P < .05.

Moreover, to find out the association of XRCC1A (Arg194Trp) genotype with the risk of BC, we carried out stratified logistic regression analysis. For stratified analysis, the study population was divided into 2 strata: strata 1 comprised of premenopausal females, whereas strata 2 comprised of postmenopausal females. After stratification based on menopausal status of study population, univariate logistic regression analysis and multivariate logistic regression analysis adjusted for age, region, menstrual status, marital status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit were carried out. Multivariate logistic regression analysis of stratified data set has shown that tryptophan allele (R/W-W/W genotype) in XRCC1A (Arg194Trp) gene significantly increased the risk of BC in premenopausal females (crude OR = 1.66, 95% CI = 1.11-2.46, p<0.05 for R/W-W/W genotype) from NE region of India (Table 3).

Table 3.

Association of XRCC1A (Arg194Trp) Polymorphism With Risk of Breast Cancer in Females From NE Region of India Stratified on the Basis of Menopausal Status.

	Group 1: Premenopausal Females						Group 2: Postmenopausal Females
Genotypes	Cases	Controls	Crude OR (95% CI)	P value	AOR (95% CI)	P value	Cases	Controls	Crude OR (95% CI)	P value	AOR (95% CI)	P value
Codominant model	n = 237	n = 366					n = 217	n = 118
R/R	136	234	Ref		Ref		121	77	Ref		Ref
R/W	84	108	1.33 (0.93-1.90)	0.1	1.56 (1.03-2.35)	0.03^a	90	39	1.46 (0.91-2.35)	0.11	1.32 (0.74-2.35)	0.34
W/W	17	24	1.21 (0.63-2.34)	0.55	2.48 (1.08-5.69)	0.03^a	6	2	1.90 (0.37-9.70)	0.43	2.21 (0.29-16.8)	0.44
Dominant model	n = 237	n = 366					n = 217	n = 118
R/R	136	234	Ref		Ref		121	77	Ref		Ref
R/W-W/W	101	132	1.31 (0.94-1.83)	0.1	1.66 (1.11-2.46)	0.012^a	96	41	1.49 (0.93-2.37)	0.09	1.35 (0.76-2.38)	0.3
Recessive model	n = 237	n = 366					n = 217	n = 118
R/R-R/W	220	342	Ref		Ref		211	116	Ref		Ref
W/W	17	24	1.10 (0.57-2.09)	0.76	2.02 (0.90-4.54)	0.08	6	2	1.64 (0.32-8.30)	0.54	1.94 (0.26-14.5)	0.51

^aStatistically significant at P < .05.

Association of XRCC3 (Thr241Met) Polymorphism With Risk of BC in Females From NE Region, India

To investigate the association of XRCC3 (Thr241Met) genotype with the risk of BC in females from NE region of India, both univariate and multivariate logistic regression analyses after adjusting for age, region, menstrual status, marital status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit were carried out. Both univariate and multivariate logistic regression analyses have revealed no significant association of XRCC3 (Thr241Met) genotype with the risk of BC (Table 4).

Table 4.

Association of XRCC3 (Thr241Met) Polymorphism With Risk of Breast Cancer in Females From NE Region of India.^a

Genotypes	Cases	Controls	Crude OR (95% CI)	P Value	AOR (95% CI)	P Value
Co-dominant model	n = 464	n = 534
T/T	350	426	Ref		Ref
T/M	100	99	1.22 (0.90-1.67)	.194	1.11 (0.76-1.60)	.578
M/M	14	9	1.89 (0.81-4.42)	.141	1.90 (0.71-5.08)	.195
Dominant model	n = 464	n = 534
T/T	350	426	Ref		Ref
T/M-M/M	114	108	1.28 (0.95-1.73)	.100	1.17 (0.82-1.67)	.364
Recessive model	n = 464	n = 534
T/T-T/M	450	525	Ref		Ref
M/M	14	9	1.81 (0.77-4.23)	.168	1.86 (0.70-4.96)	.209

Abbreviations: AOR, adjusted OR, adjusted for age, region, marital status, menopausal status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat and bamboo shoots consumption habit; CI, confidence interval; M, methionine; NE, northeast; OR, odds ratio; T, threonine; XRCC, X-ray repair cross complementary.

^aStatistically significant at P < .05.

Moreover, to find out the association of XRCC3 (Thr241Met) gene polymorphism with risk of BC in premenopausal and postmenopausal females in NE region of India, we carried out stratified logistic regression analysis by stratifying the study population into 2 groups, namely, group 1 for premenopausal females and group 2 for postmenopausal females. After stratification, both univariate logistic regression analysis and multivariate logistic regression analysis adjusted for age, region, menstrual status, marital status, betel nut chewing, tobacco smoking, alcohol consumption, dry fish, dry meat, and bamboo shoots consumption habit were carried out. Both univariate and adjusted multivariate logistic regression analyses of stratified data set revealed no significant association of XRCC3 (Thr241Met) gene with the risk of BC (Table 5).

Table 5.

Association of XRCC3 (Thr241Met) Polymorphism With Risk of Breast Cancer in Females From NE Region of India Stratified on the Basis of Menopausal Status.^a

			Group 1: Premenopausal Females				Group: 2 Postmenopausal Females
Genotypes	Cases	Controls	Crude OR (95% CI)	P Value	AOR (95% CI)	P Value	Cases	Controls	Crude OR (95% CI)	P Value	AOR (95% CI)	P Value
Codominant model	n = 237	n = 366					n = 217	n = 118
T/T	183	292	Ref		Ref		162	93	Ref		Ref
T/M	46	68	1.07 (0.71-1.63)	.72	1.01 (0.63-1.61)	.95	49	22	1.27 (0.72-2.24)	.34	1.37 (0.70-2.70)	.35
M/M	8	6	2.12 (0.72-6.23)	.16	2.14 (0.60-7.56)	.23	6	3	1.14 (0.28-4.69)	.84	0.91 (0.16-5.12)	.92
Dominant model	n = 237	n = 366					n = 217	n = 118
T/T	183	292	Ref		Ref		162	93	Ref		Ref
T/M-M/M	54	74	1.16 (0.78-1.73)	.45	1.09 (0.70-1.71)	.69	55	25	1.26 (0.73-2.16)	.39	1.31 (0.69-2.50)	.4
Recessive model	n = 237	n = 366					n = 217	n = 118
T/T-T/M	229	360	Ref		Ref		211	115	Ref		Ref
M/M	8	6	2.09 (0.71-6.11)	.17	2.13 (0.60-7.51)	.23	6	3	1.09 (0.26-4.44)	.9	0.86 (0.15-4.81)	.87

^aStatistically significant at P < .05.

Discussion

XRCC genes are commonly known for their involvement in BER mechanisms in small DNA lesions generally induced by oxidative stress.²⁵ Defects in DNA repair mechanisms have been found to be significantly associated with increased risk of BC.²⁹ Molecular epidemiological studies have revealed that polymorphisms in DNA repair mechanism genes are significantly associated with the increased or decreased risk of BC in different ethnic populations.^49,50 The present study was carried out to investigate the association of 2 most studied candidate genes of DNA repair mechanism, namely, XRCC1A (Arg194Trp) and XRCC3 (Thr241Met), with the risk of BC in females from NE region of India.

Epidemiological studies have shown that reproductive status of females is significantly associated with the risk of BC.⁵¹ Endocrinological studies have revealed that alternations from male to female sex hormone ratio, that is, from androgen to estrogen conversion, high rate of androgen biosynthesis, and low circulatory estrogen level, are significantly associated with the increased risk of BC in females at different menstrual phase.⁵² It has been found that high concentration of circulating estradiol is significantly protective in the onset of BC.⁵³ However, both clinical and epidemiological studies did not reveal yet how low estrogen synthesis promotes early onset of BC in premenopausal females.⁵⁴ It is postulated that genetic alternation in metabolic and/or inflammatory genes, tumor suppressor genes, and DNA repair mechanism genes in tumor microenvironment of breast may be important determinant to develop BC in females.^51,54

Studies have shown that reproductive factors and food habit significantly increased the risk of BC in females by modulating cellular oxidative stress.⁵⁵ Molecular epidemiological studies have shown that polymorphisms in DNA repair pathway-associated genes may produce altered protein product which can modulate tumorigenesis and its transformation toward carcinogenesis in breast tissue.⁵⁶ Studies from NE region of India have shown that reproductive status and food habits are significantly associated with the increased risk of BC in females in this region.⁵⁷ Moreover, epidemiological studies have shown that betel nut chewing significantly increase the risk of BC in females from NE region.⁴⁶ Biochemical studies have revealed that betel nuts are mainly composed of different types of alkaloids, such as arecoline, arecaidine, guvacine, and guvacoline, which effectively bind with the DNA after being nitrated and may produce DNA adducts⁵⁸ and thus significantly associated with the increased risk of BC in females.^59,60 Molecular epidemiological studies have postulated that tobacco smoke–derived carcinogens can modulate the expression of DNA repair mechanism pathway genes.³⁰ Experimental studies have suggested that tobacco smoke contain polycyclic aromatic hydrocarbons (PAHs), aromatic amines, and nitrosamines which cross the alveolar membrane in the lung tissue and after conjugation with lipoproteins carried to the breast epithelium via circulation,⁶¹ where these carcinogenic chemicals induce DNA adducts.⁶² Epidemiological studies have shown significant association between smoking and the increased risk of BC among postmenopausal females.³³ Similarly, studies have shown that ethanol consumption significantly stimulates the cell proliferation by altering the expression of transcription factors associated with the ER signaling pathway in females.^63,64 Biochemical studies have shown that heterocyclic amines present in dried fish and fried meat act as strong carcinogens.⁶⁵ In NE region of India, people from different ethnic groups consume dry fish and dry meat either regularly or occasionally.⁶⁶ Studies have shown that dry fish and dry meat consumption significantly associated with the increased risk of cancers in NE region.⁶⁷ Keeping these in view, it is hypothesized that betel nut chewing, tobacco smoking and/or chewing, alcohol, dry fish, and dry meat consumption act as putative risk factors for tumorigenesis in females from NE region of India.⁶⁸ In the present study, to investigate the association of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) polymorphisms with the increased risk of BC in females from NE region of India, we performed multivariate logistic regression analysis making adjustment of age, region, menstrual status, marital status, betel nut chewing, tobacco chewing and/or smoking, alcohol, dry fish, and dry meat consumption habits.

Molecular epidemiological studies have shown that Arg/Trp (R/W) allele in XRCC1A (Arg194Trp) gene is significantly associated with the increased risk of BC in perimenopausal females, aged between 45 and 54 years.⁶⁹ Moreover, studies have revealed that protein product of XRCC1A (Arg194Trp) gene is associated with the regulation of protein–protein interactions in ADPRT and DNA polymerase β.^3,25 It has been found that sequence alternation in XRCC1A (Arg194Trp) gene encodes a twisted gene product capable to modulate cellular innate DNA repair mechanism and thus increase the risk of oncogenesis.^{70

–73} Molecular epidemiological studies have revealed significant association of XRCC1 polymorphism with the increased risk of BC in females, although the results are inconsistent in different ethnic populations globally^38,39,41,74 (Figure 1). Our present case–control study has shown that tryptophan allele (R/W-W/W genotype) in XRCC1A (Arg194Trp) gene significantly increased the risk of BC 1.44-fold (adjusted OR = 1.44, 95% CI 1.06-1.97, P < .05). This study has also revealed that W/W genotype in XRCC1A (Arg194Trp) gene significantly increased the risk of BC 2.48-fold (OR = 2.48, 95% CI 1.08-5.69, P < .05) in premenopausal females from NE region of India (Table 3).

Figure 1.

Association of XRCC1A (Arg194Trp) polymorphism with the increased risk of breast cancer (BC) and its comparison with our present case–control study. Comparative analysis of association between XRCC1A (Arg194Trp) polymorphism and the risk of BC in different ethnic populations globally.

XRCC3 gene encodes a protein, related to the member of Rad 51 family, responsible for homologous recombination repair of DNA double-strand break.^75,76 Studies have shown that single base pair substitution in the exon number 7 of the XRCC3 gene, commonly known as codon 241, may influence the enzyme function of DNA repair mechanism and thus causes DNA damage. In vitro studies have shown that XRCC3 gene knockout cells are highly sensitive to DNA damaging agents.⁷⁷ Molecular epidemiological studies have revealed that XRCC3 Thr241Met polymorphism may alter DNA repair capacity and significantly influence the susceptibility to carcinogens (Figure 2). Studies have found significant association between XRCC3 polymorphism and increased risk of colon cancer,^78,79 gastric cancer,^22,23 bladder cancer,¹³ thyroid cancer,⁸⁰ renal cell carcinoma,⁸¹ and lung cancer.^82,83 Moreover, studies have shown that methionine allele (M/M genotype) in XRCC3 (Thr241Met) gene significantly increased the risk of BC.^{72,73,84

–87} However, studies also have found no association of XRCC3 (Thr241Met) gene with the risk of BC and thus compelled to hypothesize that ethnic variation also persists between XRCC3 (Thr241Met) polymorphism and the risk of BC in females.^{38,40,88
–90} However, It has been assumed that XRCC3 (Thr241Met) is an important candidate gene in tumorigenesis.⁹¹ Thus, to investigate the association of XRCC3 (Thr241Met) polymorphism with the increased risk of BC in females from NE region of India, we carried out both univariate and multivariate logistic regression analyses after adjustment for reproductive factors and food habits. Moreover, to find out the association between XRCC3 polymorphism and the risk of BC in females, we stratified our study population into premenopausal and postmenopausal strata. However, the present case–control study did not reveal any significant association of XRCC3 (Thr241Met) polymorphism with the risk of BC in females from NE region of India (Table 5).

Figure 2.

Association of XRCC3 (Thr241Met) polymorphism with the increased risk of breast cancer (BC) and its comparison with our present case–control study. Comparative analysis of association between XRCC3 (Thr241Met) polymorphism and the risk of BC in different ethnic populations globally.

In the present case–control study, we did not perform follow-up study of patients with BC to investigate the association of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) polymorphisms with the anticancer treatment regime due to logistic issues. Moreover, we were also unable to explore the expressional profiling of these 2 genes due to limited resources. Thus, the primary limitations of this study are cross-sectional design instead of longitudinal design and unavailability of expressional profiling data of XRCC1A and XRCC3 genes, respectively.

Conclusion

The present study has revealed that XRCC1A (Arg194Trp) polymorphism is significantly associated with the increased risk of BC in females from NE region of India. Moreover, this study has shown that tryptophan allele in XRCC1A (Arg194Trp) gene significantly increased the risk of BC 2.48-fold in premenopausal females. However, the present study did not reveal any significant association of XRCC3 (Thr241Met) polymorphism with the risk of BC. Future studies with larger sample size and with more single-nucleotide polymorphisms related to DNA repair mechanism of human genome are required to elucidate the association of DNA repair mechanism genes with the risk of BC in females from NE region of India.

Footnotes

Abbreviations

Acknowledgments

The authors would like to thank all study participants for their cooperation.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Indian Council of Medical Research (ICMR), India.

References

Figueiredo

Knight

Briollais

Andrulis

Ozcelik

. Polymorphisms XRCC1-R399Q and XRCC3-T241 M and the risk of breast cancer at the Ontario site of the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2004;13(4):583–591.

Webb

Hopper

Newman

. Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(2):319–323. doi:10.1158/1055-9965.EPI-04-0335.

Duell

Millikan

Pittman

. Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomarkers Prev. 2001;10(3):217–222.

Khlifi

Kallel

Hammami

Hamza-Chaffai

Rebai

. DNA repair gene polymorphisms and risk of head and neck cancer in the Tunisian population. J Oral Pathol Med. 2014;43(3):217–224. doi:10.1111/jop.12114.

Thacker

Zdzienicka

. The XRCC genes: expanding roles in DNA double-strand break repair. DNA Repair (Amst). 2004;3(8-9):1081–1090. doi:10.1016/j.dnarep.2004.04.012.

Liu

Shi

Zhou

. Role of XRCC1 and ERCC5 polymorphisms on clinical outcomes in advanced non-small cell lung cancer. Genet Mol Res. 2014;13(2):3100–3107. doi:10.4238/2014.April.17.6.

Mei

Qian

Shi

Jie

. Association between genetic polymorphisms in XPD and XRCC1 genes and risks of non-small cell lung cancer in East Chinese Han population. Clin Respir J. 2016;10(3):311–317. doi:10.1111/crj.12218.

Peng

Zhang

. Association of DNA base excision repair genes (OGG1, APE1 and XRCC1) polymorphisms with outcome to platinum-based chemotherapy in advanced nonsmall-cell lung cancer patients. Int J Cancer. 2014;135(11):2687–2696. doi:10.1002/ijc.28892.

Wan

Wen

. Polymorphisms in the XRCC1 gene are associated with treatment response to platinum chemotherapy in advanced non-small cell lung cancer patients based on meta-analysis. Genet Mol Res. 2014;13(2):3772–3786. doi:10.4238/2014.May.16.1.

10.

Santana

de Moura Santos

Galvao

Coletta

Freitas

. DNA base excision repair proteins APE-1 and XRCC-1 are overexpressed in oral tongue squamous cell carcinoma. J Oral Pathol Med. 2017;46(7):496–503. doi:10.1111/jop.12529.

11.

Dong

Zhang

Teng

Wang

. Meta-analysis demonstrates no association between XRCC1 Arg399Gln polymorphism and bladder cancer risk. Genet Mol Res. 2014;13(4):9976–9985. doi:10.4238/2014.November.28.2.

12.

Ramaniuk

Nikitchenko

Savina

, et al. Polymorphism of DNA repair genes OGG1, XRCC1, XPD and ERCC6 in bladder cancer in Belarus. Biomarkers. 2014;19(6):509–516. doi:10.3109/1354750X.2014.943291.

13.

Zhang

Hao

Zhou

Zhang

Liang

. Association between twelve polymorphisms in five x-ray repair cross-complementing genes and the risk of urological neoplasms: a systematic review and meta-analysis. EBioMedicine. 2017;18:94–108. doi:10.1016/j.ebiom.2017.03.009.

14.

Monteiro

Vilas Boas

Gigliotti

Salvadori

. Association among XRCC1, XRCC3, and BLHX gene polymorphisms and chromosome instability in lymphocytes from patients with endometriosis and ovarian cancer. Genet Mol Res. 2014;13(1):636–648. doi:10.4238/2014.January.28.9.

15.

Wang

. The association between XRCC1 genetic polymorphisms and the risk of endometrial carcinoma in Chinese. Gene. 2015;554(2):155–159. doi:10.1016/j.gene.2014.10.041.

16.

Zhou

Zou

. DNA repair gene polymorphisms and clinical outcome of patients with primary small cell carcinoma of the esophagus. Tumour Biol. 2015;36(3):1539–1548. doi:10.1007/s13277-014-2718-y.

17.

Zhao

Gao

Liu

. Influence of the c.1517G>C genetic variant in the XRCC1 gene on pancreatic cancer susceptibility in a Chinese population. Genet Mol Res. 2014;13(2):4466–4472. doi:10.4238/2014.June.16.5.

18.

Meng

Zhang

. Association of XRCC1 gene polymorphisms with susceptibility to gastric cancer in Chinese Han population. J Pharm Pharmacol. 2014;66(10):1463–1468. doi:10.1111/jphp.12264.

19.

Yang

Gui

Bian

. DNA repair gene XRCC1 Arg194Trp polymorphism and susceptibility to hepatocellular carcinoma: a meta-analysis. Oncol Lett. 2014;8(4):1725–1730. doi:10.3892/ol.2014.2351.

20.

Chen

Wang

. X-ray repair cross-complementing 1 polymorphism and prognosis of platinum-based chemotherapy in gastric and colorectal cancer: a meta-analysis. J Gastroenterol Hepatol. 2014;29(5):926–933. doi:10.1111/jgh.12444.

21.

Srivastava

Pandey

Choudhuri

Mittal

. Single-nucleotide polymorphisms of DNA repair genes OGG1 and XRCC1: association with gallbladder cancer in North Indian population. Ann Surg Oncol. 2009;16(6):1695–1703. doi:10.1245/s10434-009-0354-3.

22.

Carrera-Lasfuentes

Lanas

Bujanda

. Relevance of DNA repair gene polymorphisms to gastric cancer risk and phenotype. Oncotarget. 2017;8(22):35848–35862. doi:10.18632/oncotarget.16261.

23.

Gong

Zou

. The relationship between five non-synonymous polymorphisms within three XRCC genes and gastric cancer risk in a Han Chinese population. Tumour Biol. 2016;37(5):5905–5910. doi:10.1007/s13277-015-3502-3.

24.

Popanda

Tan

Ambrosone

. Genetic polymorphisms in the DNA double-strand break repair genes XRCC3, XRCC2, and NBS1 are not associated with acute side effects of radiotherapy in breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2006;15(5):1048–1050. doi:10.1158/1055-9965.EPI-06-0046.

25.

Kuschel

Auranen

McBride

. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol genet. 2002;11(12):1399–1407.

26.

Rao

Paul

Kumar

. Allele and genotype distributions of DNA repair gene polymorphisms in South Indian healthy population. Biomark Cancer. 2014;6:29–35. doi:10.4137/BIC.S19681.

27.

Takeshita

Fujihara

Yasuda

Kimura-Kataoka

. Worldwide distribution of four SNPs in X-ray and repair and cross-complementing group 1 (XRCC1). Clin Transl Sci. 2015;8(4):347–350. doi:10.1111/cts.12237.

28.

Goricar

Kovac

Dolzan

. Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma. Sci Rep. 2017;7:46537. doi:10.1038/srep46537.

29.

Smolarz

Makowska

Samulak

. Single nucleotide polymorphisms (SNPs) of ERCC2, hOGG1, and XRCC1 DNA repair genes and the risk of triple-negative breast cancer in Polish women. Tumour Biol. 2014;35(4):3495–3502. doi:10.1007/s13277-013-1461-0.

30.

Shen

Gammon

Terry

. Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14(2):336–342. doi:10.1158/1055-9965.EPI-04-0414.

31.

Huang

. XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms in breast cancer risk: a meta-analysis. Mutagenesis. 2009;24(4):331–339. doi:10.1093/mutage/gep013.

32.

Bewick

Conlon

Lafrenie

. Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer. J Clin Oncol. 2006;24(36):5645–5651. doi:10.1200/JCO.2006.05.9923.

33.

Metsola

Kataja

Sillanpaa

. XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study. Breast Cancer Res. 2005;7(6):R987–R997. doi:10.1186/bcr1333.

34.

Patel

Calle

Pavluck

Feigelson

Thun

Rodriguez

. A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk. Breast Cancer Res. 2005;7(6):R1168–R1173. doi:10.1186/bcr1355.

35.

Millikan

Player

Decotret

Tse

Keku

. Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14(10):2326–2334. doi:10.1158/1055-9965.EPI-05-0186.

36.

Macias-Gomez

Peralta-Leal

Meza-Espinoza

. Polymorphisms of the XRCC1 gene and breast cancer risk in the Mexican population. Fam Cancer. 2015;14(3):349–354. doi:10.1007/s10689-015-9787-y.

37.

Loizidou

Michael

Neuhausen

. Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus. Breast Cancer Res Treat. 2008;112(3):575–579. doi:10.1007/s10549-007-9881-4.

38.

Al Zoubi

Zavaglia

Mazanti

. Polymorphisms and mutations in GSTP1, RAD51, XRCC1 and XRCC3 genes in breast cancer patients. Int J Biol Markers. 2017;32(3):e337–e343. doi:10.5301/ijbm.5000258.

39.

Jalali

Ghaderi

Amini

Abdi

Roshani

. Association of XRCC1 Trp194 allele with risk of breast cancer, and Ki67 protein status in breast tumor tissues. Saudi Med J. 2016;37(6):624–630. doi:10.15537/Smj.2016.6.13540.

40.

Romanowicz

Pyziak

Jablonski

Brys

Forma

Smolarz

. Analysis of DNA repair genes polymorphisms in breast cancer. Pathol Oncol Res. 2017;23(1):117–123. doi:10.1007/s12253-016-0110-5.

41.

Sanjari Moghaddam

Nazarzadeh

Noroozi

Darvish

Mosavi Jarrahi

. XRCC1 and OGG1 gene polymorphisms and breast cancer: a systematic review of literature. Iran J Cancer Prev. 2016;9(1):e3467. doi:10.17795/ijcp-3467.

42.

Murthy

Chaudhry

Rath

. Burden of cancer and projections for 2016, Indian scenario: gaps in the availability of radiotherapy treatment facilities. Asian Pac J Cancer Prev. 2008;9(4):671–677.

43.

Sharma

Kataki

Vijay

. Population-based incidence and patterns of cancer in Kamrup Urban Cancer Registry, India. Natl Med J India. 2013;26(3):133–141.

44.

Krishnatreya

Kataki

Sharma

. Descriptive epidemiology of common female cancers in the north east India—a hospital based study. Asian Pac J Cancer Prev. 2014;15(24):10735–10738.

45.

Ghatak

Lallawmzuali

Lalmawia . Mitochondrial D-loop and cytochrome oxidase C subunit I polymorphisms among the breast cancer patients of Mizoram, Northeast India. Curr Genet. 2014;60(3):201–212. doi:10.1007/s00294-014-0425-2.

46.

Kaushal

Mishra

Raju

. Betel quid chewing as an environmental risk factor for breast cancer. Mutat Res. 2010;703(2):143–148. doi:10.1016/j.mrgentox.2010.08.011.

47.

Devi

Chenkual

Majumdar

. TLR222 (-196-174) significantly increases the risk of breast cancer in females carrying proline allele at codon 72 of TP53 gene: a case-control study from four ethnic groups of North Eastern region of India. Tumour Biol. 2015;36(12):9995–10002. doi:10.1007/s13277-015-3795-2.

48.

Zhang

Wan

Jin

. Genetic polymorphisms in XRCC1, APE1, ADPRT, XRCC2, and XRCC3 and risk of chronic benzene poisoning in a Chinese occupational population. Cancer Epidemiol Biomarkers Prev. 2005;14(11 Pt 1):2614–2619. doi:10.1158/1055-9965.EPI-05-0143.

49.

Chang-Claude

Popanda

Tan

. Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients. Clin Cancer Res. 2005;11(13):4802–4809. doi:10.1158/1078-0432.CCR-04-2657.

50.

Smith

Liu-Mares

Van Emburgh

. Genetic polymorphisms of multiple DNA repair pathways impact age at diagnosis and TP53 mutations in breast cancer. Carcinogenesis. 2011;32(9):1354–1360. doi:10.1093/carcin/bgr117.

51.

Suba

. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications. Onco Targets Ther. 2014;7:147–164. doi:10.2147/OTT.S52600.

52.

Stoll

BA.

Teenage obesity in relation to breast cancer risk. International journal of obesity and related metabolic disorders. Int J Obes Relat Metab Disord. 1998;22(11):1035–1040.

53.

Millikan

Newman

Tse

. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat. 2008;109(1):123–139. doi:10.1007/s10549-007-9632-6.

54.

Suba

. Circulatory estrogen level protects against breast cancer in obese women. Recent Pat Anticancer Drug Discov. 2013;8(2):154–167.

55.

Aitken

Smith

Jobling

Baker

De Iuliis

. Oxidative stress and male reproductive health. Asian J Androl. 2014;16(1):31–38. doi:10.4103/1008-682X.122203.

56.

Liu

Chen

Gong

. Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide. J Pharmacol Exp Ther. 2011;339(2):451–463. doi:10.1124/jpet.111.180505.

57.

Kaushal

Mishra

Sharma

. Genomic alterations in breast cancer patients in betel quid and non betel quid chewers. PloS One. 2012;7(8):e43789. doi:10.1371/journal.pone.0043789.

58.

Bhattacharjee

Sharan

. Aqueous extract of betel nut-induced adducts on pMTa4 DNA acquires stability in the presence of Na+ and K+ ions. Mol Med Rep. 2008;1(3):435–441.

59.

Synowiec

Stefanska

Morawiec

Blasiak

Wozniak

. Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients. Mutat Res. 2008;648(1-2):65–72. doi:10.1016/j.mrfmmm.2008.09.014.

60.

Wasson

Chauhan

Singh

. Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis. Tumour Biol. 2014;35(6):5885–5894. doi:10.1007/s13277-014-1779-2.

61.

Kotnis

Namkung

Kannan

. Multiple pathway-based genetic variations associated with tobacco related multiple primary neoplasms. PloS One. 2012;7(1):e30013. doi:10.1371/journal.pone.0030013.

62.

Rundle

Tang

Hibshoosh

. Molecular epidemiologic studies of polycyclic aromatic hydrocarbon-DNA adducts and breast cancer. Environ Mol Mutagen. 2002;39(2-3):201–207.

63.

Frydenberg

Flote

Larsson

. Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women. Breast Cancer Res. 2015;17:103. doi:10.1186/s13058-015-0620-1.

64.

Slattery

Lundgreen

John

. MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: the Breast Cancer Health Disparities Study. Nutr Cancer. 2015;67(2):292–304. doi:10.1080/01635581.2015.990568.

65.

Pais

Salmon

Knize

Felton

. Formation of mutagenic/carcinogenic heterocyclic amines in dry-heated model systems, meats, and meat drippings. J Agric Food Chem. 1999;47(3):1098–1108.

66.

Saha

Gupta

Kumar

. Cardiovascular health among healthy population of Northeast region of India: a cross-sectional study comparing urban-tribal difference. J Indian Med Assoc. 2013;111(12):810–814,816.

67.

Malakar

Devi

, Phukan RK, et al. p53 codon 72 polymorphism interactions with dietary and tobacco related habits and risk of stomach cancer in Mizoram, India. Asian Pac J Cancer Prev . 2014;15(2):717–723.

68.

Chandirasekar

Kumar

Sasikala

. Assessment of genotoxic and molecular mechanisms of cancer risk in smoking and smokeless tobacco users. Mutat Res Genet Toxicol Environ Mutagen. 2014;767:21–27. doi:10.1016/j.mrgentox.2014.04.007.

69.

Silva

Moita

Azevedo

. Menopausal age and XRCC1 gene polymorphisms: role in breast cancer risk. Cancer Detect Prev. 2007;31(4):303–309. doi:10.1016/j.cdp.2007.07.001

70.

Smith

Miller

Lohman

. Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. Cancer Lett. 2003;190(2):183–190.

71.

Chacko

Rajan

Joseph

Mathew

Pillai

. Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer. Breast Cancer Res Treat. 2005;89(1):15–21. doi:10.1007/s10549-004-1004-x.

72.

Przybylowska-Sygut

Stanczyk

Kusinska

Kordek

Majsterek

. Association of the Arg194Trp and the Arg399Gln polymorphisms of the XRCC1 gene with risk occurrence and the response to adjuvant therapy among Polish women with breast cancer. Clin Breast Cancer. 2013;13(1):61–68. doi:10.1016/j.clbc.2012.09.019.

73.

Ramadan

Desouky

Elnaggar

Moaaz

Elsherif

. Association of DNA repair genes XRCC1 (Arg399Gln), (Arg194Trp) and XRCC3 (Thr241Met) polymorphisms with the risk of breast cancer: a case-control study in Egypt. Genet Test Mol Biomarkers. 2014;18(11):754–760. doi:10.1089/gtmb.2014.0191.

74.

Batar

Guven

Eroz

Bese

Guven

. Decreased DNA repair gene XRCC1 expression is associated with radiotherapy-induced acute side effects in breast cancer patients. Gene. 2016;582(1):33–37. doi:10.1016/j.gene.2016.01.040.

75.

Shu

Cai

Gao

Wen

Jin

Zheng

. 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):1462–1467.

76.

Silva

Tomar

Paulo

. Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51. Cancer Epidemiol. 2010;34(1):85–92. doi:10.1016/j.canep.2009.11.002.

77.

Singleton

Griffin

Thacker

. Clustered DNA damage leads to complex genetic changes in irradiated human cells. Cancer Res. 2002;62(21):6263–6269.

78.

Agostini

Zangrando

Pastrello

. A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients. Cancer Biol Ther. 2015;16(8):1160–1171. doi:10.1080/15384047.2015.1046652.

79.

Krupa

Sliwinski

Wisniewska-Jarosinska

. Polymorphisms in RAD51, XRCC2 and XRCC3 genes of the homologous recombination repair in colorectal cancer—a case control study. Molecular Biol Rep. 2011;38(4):2849–2854. doi:10.1007/s11033-010-0430-6.

80.

Sarwar

Mahjabeen

Bashir

Saeed

Kayani

. Haplotype based analysis of XRCC3 gene polymorphisms in thyroid cancer. Cell Physiol Biochem. 2017;42(1):22–33. doi:10.1159/000477109.

81.

Loghin

Banescu

Nechifor-Boila

. XRCC3 Thr241Met and XPD Lys751Gln gene polymorphisms and risk of clear cell renal cell carcinoma. Cancer Biomark. 2016;16(2):211–217. doi:10.3233/CBM-150558.

82.

Catana

Pop

Marginean

. XRCC3 Thr241Met polymorphism is not associated with lung cancer risk in a Romanian population. Clujul Med. 2016;89(1):89–93. doi:10.15386/cjmed-523.

83.

Liu

. Correlation between gene polymorphisms of CYP1A1, GSTP1, ERCC2, XRCC1, and XRCC3 and susceptibility to lung cancer. Genet Mol Res. 2016;15(4). doi:10.4238/gmr15048813.

84.

Mao

Qian

Sun

Tang

. Association between the XRCC3 Thr241Met polymorphism and breast cancer risk: an updated meta-analysis of 36 case-control studies. Asian Pac J Cancer Prev. 2014;15(16):6613–6618.

85.

Pramanik

Devi

Chowdhary

Surendran

Krishnamurthi

Chakrabarti

. DNA repair gene polymorphisms at XRCC1, XRCC3, XPD, and OGG1 loci in Maharashtrian population of central India. Chemosphere. 2011;82(7):941–946. doi:10.1016/j.chemosphere.2010.10.100.

86.

Romanowicz-Makowska

Smolarz

. The association between polymorphisms of the RAD51-G135C, XRCC2-Arg188His and XRCC3-Thr241Met genes and clinico-pathologic features in breast cancer in Poland. Eur J Gynaecol Oncol. 2012;33(2):145–150.

87.

Sangrajrang

Schmezer

Burkholder

. The XRCC3 Thr241Met polymorphism and breast cancer risk: a case-control study in a Thai population. Biomarkers. 2007;12(5):523–532. doi:10.1080/13547500701395602.

88.

Jacobsen

Nexo

Olsen

. No association between the DNA repair gene XRCC3 T241 M polymorphism and risk of skin cancer and breast cancer. Cancer Epidemiol Biomarkers Prev. 2003;12(6):584–585.

89.

Saadat

Ansari-Lari

. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures. Breast Cancer Res Treat. 2009;115(1):137–144. doi:10.1007/s10549-008-0051-0.

90.

Thyagarajan

Anderson

Folsom

. No association between XRCC1 and XRCC3 gene polymorphisms and breast cancer risk: Iowa Women’s Health Study. Cancer Detect Prev. 2006;30(4):313–321. doi:10.1016/j.cdp.2006.07.002.

91.

Cheng

Huang

. Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination. PLoS Genet. 2017;13(5):e1006827. doi:10.1371/journal.pgen.1006827.

DNA Repair Mechanism Gene,XRCC1A ( Arg194Trp ) but not XRCC3 ( Thr241Met ) Polymorphism Increased the Risk of Breast Cancer in Premenopausal Females: A Case–Control Study in Northeastern Region of India

Abstract

Keywords

Introduction

Materials and Methods

Ethics Statement

Study Participants and Specimen Collection

Genotyping of XRCC1A (Arg194Trp) and XRCC3 (Thr241Met) Polymorphisms

Statistical Analysis

Results

Patient Characteristics

Test for HWE

Association of XRCC1A (Arg194Trp) Polymorphisms With the Risk of BC in Females From NE Region of India

Association of XRCC3 (Thr241Met) Polymorphism With Risk of BC in Females From NE Region, India

Discussion

Conclusion

Footnotes

Abbreviations

Acknowledgments

Declaration of Conflicting Interests

Funding

References