research article polymorphisms in dna repair gene xrcc3 and … · 2019. 7. 30. · susceptibility...

Research ArticlePolymorphisms in DNA Repair Gene XRCC3and Susceptibility to Breast Cancer in Saudi Females

Alaa Mohammed Ali1 Huda AbdulKareem2 Mohammad Al Anazi1

Narasimha Reddy Parine3 Jilani Purusottapatnam Shaik3 Abdullah Alamri3

Akbar Ali Khan Pathan3 and Arjumand Warsy4

1Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia2Comprehensive Cancer Center Department of Womenrsquos Imaging King Fahad Medical City Riyadh Saudi Arabia3Genome Research Chair Department of Biochemistry College of Science King Saud University Riyadh Saudi Arabia4Department of Biochemistry Center for Science and Medical Studies for Girls College of Science King Saud UniversityPO Box 22452 Riyadh 11495 Saudi Arabia

Correspondence should be addressed to Arjumand Warsy aswarsyksuedusa

Received 13 September 2015 Revised 8 December 2015 Accepted 9 December 2015

Academic Editor Janusz Blasiak

Copyright copy 2016 Alaa Mohammed Ali et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

We investigated three common polymorphisms (SNPs) in the XRCC3 gene (rs861539 rs1799794 and rs1799796) in 143 Saudifemales suffering from breast cancer (median age = 514 years) and 145 age matched normal healthy controls DNA was extractedfrom whole blood and genotyping was conducted using PCR-RFLP rs1799794 showed significant association where AA andAA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR 281 95 CI376ndash2112 1205942 2282 119901 lt 00001) The G allele was protective and presented with a dominant model The genotype and allelefrequencies of rs861539 CgtT and rs1799796 AgtG did not show a significant difference when the results in the patients and controlswere compared However the frequency of rs1799796 differed significantly in patients with different age of diagnosis tumor gradeand ER and HER2 status The wild type A allele occurred at a higher frequency in the ERminus and HER2minus group Our results amongSaudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility In conclusion the results obtainedduring this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females

1 Introduction

Damage induced by endogenous and exogenous factorsaffects the integrity and stability of DNA but is constantlyand effectively corrected by the DNA repair pathways Someserious mutations in these genes are shown to result indisorders such as Xeroderma pigmentosa however a widevariety of common polymorphisms are reported to be linkedto mild defects in DNA repair which may predispose aperson to the development of different forms of cancer [1ndash3] Extensive studies have been conducted among differentpopulations to identify such polymorphisms but the resultsfrom different populations are controversial [4 5] SeveralDNA repair pathways are functional and repair differenttypes of damage where the double strand breaks (DSB) are

corrected by either homologous recombination repair (HRR)or nonhomologous end-joining pathways [6] The cellrsquossusceptibility to DNA damage and its ability to repair thisdamage are important for cancer induction promotion andprogression Among the different DNA repair genes of theHRR the X-ray repair complementing defective repair inChinese hamster cells 3 (XRCC3) has been the subject ofconsiderable investigation XRCC2 and XRCC3 genes arestructurally and functionally related to RAD51 which playsan important role in homologous recombination a processif defective frequently involved in cancer transformation [7]

X-ray repair complementing defective repair in Chinesehamster cells 3 (XRCC3) is a member of the RecARad51-related protein family that participates in HRR maintain-ing chromosome stability and participating in DNA repair

Hindawi Publishing CorporationBioMed Research InternationalVolume 2016 Article ID 8721052 9 pageshttpdxdoiorg10115520168721052

2 BioMed Research International

Table 1 Primers used for amplification of SNPs in XRCC3

SNPs in XRCC3 Primers

Thr241Met c722 (rs861539) F 51015840-GCTGTCTCGGGGCATGGCTC-31015840

R 31015840-TTTAGCCAGGATGCGGAAGC-51015840

c316 (rs1799794) F 51015840-TGAGGCGCCTAATCAGC-31015840

R 31015840-CGCTGCTTGACACAGTCCA-51015840

c562-14 (rs1799796) F 51015840-GACACCTCTACAGAGGACG-31015840

R 31015840-CTGTGCCTAACCATCGAGAA-51015840

XRCC3 is one of the protein components involved in theHRR pathway and Liu et al [8] showed that XRCC3 interactsdirectlywithRAD51 andmay cooperatewith it during recom-binational repair mechanisms Several polymorphisms havebeen identified in this gene where some of the resultinggenetic variants may alter the capacity of DNA repairmechanism and hence may be associated with increased ordecreased susceptibility to tumor genesis [9] Genetic poly-morphisms inHRR genes that can lead to protein haploinsuf-ficiency are generally associated with increased cancer riskThough theXRCC3 gene is a highly suspected candidate genefor cancer susceptibility several association studies on theXRCC3 polymorphisms in cancer have reported conflictingresults [10]

The previous published data on the association betweenXRCC3 Thr241Met A4541G and A17893G polymorphismsand breast cancer risk remains largely controversial andpopulation related differences in association are reported fre-quently Kuschel et al [2] performed genetic association stud-ies in a population-based breast cancer case-control studyand analyzed polymorphisms in 7 genes involved in DNArepair Genotype frequencies differed between cases andcontrols for 2 polymorphisms in the XRCC3 gene Howevermost subsequent studies on Caucasians failed to confirm thisassociation [10 11] though a few studies did report thatXRCC3 Thr241Met is related to an increased risk of breastcancer Several meta-analyses using pooled data were per-formed and some showed a small but significant increase incancer risk [12ndash15]

In Saudi Arabia as in several other countries of the worldbreast cancer is the most common cancer in females [16]Though the incidence of breast cancer is lower than in West-ern countries it ranks highest amongst all the malignanciesseen among Saudi females [16] Interest in the moleculargenetics of cancer among Saudis has gained momentum overthe last few years and differentDNA repair genes are the focusof several studies With this background we initiated thiscase-control study on Saudi breast cancer patients and inves-tigated three commonly reported XRCC3 polymorphisms(Thr241Met c722 (rs861539) c562-14 (rs1799796) and c316(rs1799794)) in the patients in comparison with the healthycontrols

2 Material and Methods

21 Study Population This study was approved by the Insti-tutional Review Board (IRB) of King Fahad Hospital (KFH)

Written informed consent was obtained from all participantsThis was conducted as a case-control study involving 143females (median age = 513 plusmn 10 yrs) suffering from breastcancer and 145 age matched normal healthy controls allof Saudi Arabian ethnicity The breast cancer patients wereattending the outpatient clinics of the clinical coinvestigators(KFH) in Riyadh Saudi Arabia and the controls were alsoattending KFH for minor illnesses They were recruitedfollowing physical examinations after diagnostic exclusionof cancer or history of cancer and cancer-related diseasesDemographic data age at diagnosis tumor grade and recep-tor status of estrogen receptor (ER) progesterone receptor(PR) and human epidermal growth factor receptor 2 (HER2)were recorded

22 DNA Extraction Approximately 3mL blood sampleswere collected by venepuncture in ethylene diamine tetraacetic acid (EDTA) containing vacutainer tubes from allsubjects enrolled in the study DNA (genomic) was extractedfrom blood samples using a QIAamp DNA blood mini kit(Qiagen Valencia CA USA) following the manufacturerrsquosinstructionsThe extracted DNAwas spectrophotometricallyquantitated using NanoDrop 8000 (Thermo Scientific USA)and purity was determined using the standard A260A280and A260A230 ratios

23 Genotyping Three SNPs in XRCC3 were genotypedusing PCR-RFLPThe fragment of interest was amplified withthe PCR primers listed in Table 1

For the PCR 25 120583L PCRmixture was prepared and it con-tained 20 ng of DNA 10 pmol of each primer 02mmolL ofdNTPs 2mmolL ofMgCl

2 and 1U of TaqDNApolymerase

Thermal cycling conditions used during this study consistedof an initial denaturation step at 95∘C for 10min followedby 35 cycles of 95∘C for 45 sec 60∘C for 50 sec and 72∘Cfor 45 sec and a final step at 72∘C for 10 minutes All PCRproducts were subjected to electrophoresis and stored at 4∘Cuntil required for further analysisThe fragment size obtainedusing each primer set is presented in Table 2 The fragmentsobtained were treated with the specific restriction endonu-clease that is FokI for rs1799794 PvuII for rs1799796 andNlaIII for rs861539 The concentrations of each enzyme usedwere as follows 1 U of the enzyme FokI with BSA (1120583L) and5 120583L PCR products 05 120583L NlaIII with 05120583L BSA and 1 120583Lbuffer 4 used with 5120583L PCR product and 02 120583L PvuII and1 120583L of buffer X2 NEB with 5 120583L of the PCR product For FokIand NlaIII digestion conditions were as follows incubation

BioMed Research International 3

Table 2 The size of PCR products and fragment generated upon treatment with restriction enzyme for the three SNPs in XRCC3

XRCC3 SNPPCR

product size(bp)

REused Genotype Fragment sizes (bp) after

RE treatment

Thr241Met (rs861539) 231 NlaIII CgtTCC 231 12 bp

CT 231 107 112 amp 12 bpTT 112 107 amp 12 bp

rs1799794 293 FokI AgtGAA 100 amp 193 bp

AG 100 193 amp 293 bpGG 293 bp

rs1799796 650 PvuII AgtGAA 650 bp

AG 283 367 amp 650 bpGG 283 amp 376 bp

RE restriction endonuclease SNP single nucleotide polymorphism PCR polymerase chain reaction bp base pair

Table 3 Demographic data tumor grade and receptor status of the breast cancer patients investigated during this study

Averageage (years)

Tumor grade(number ofpatients)

ER status(number ofpatients)

PR status(number ofpatients)

HER2 status(number ofpatients)

Cancer patients Group 1 lt48 = 72Group 2 gt48 = 71

I = 18II = 71III = 45IV = 9

ER+ = 55ERminus = 88

PR+ = 59PRminus = 84

HER2+ = 71HER2minus = 69

at 37∘C for 3 hours followed by incubation at 65∘C for 20minwhile for PvuII the PCR product was incubated at 37∘C for 3hours After digestion the digestion products were subjectedto electrophoresis in 3 agarose gel and the size of thefragments obtained for each genotype is presented in Table 2

Five percent of the samples were randomly selected andsubjected to sequencing analysis as a quality control measurefor verification of genotyping procedures The results werereproducible without any discrepancies

24 Statistical Analysis Genotypes were assigned to eachsample and genotype and allelic frequencies were manuallycalculated and checked for deviation from the Hardy-Wein-berg equilibrium (HWE) (httpsihggsfdecgi-binhwhwa1pl) The control and patients obeyed HWE (119901 gt 005) Thegenotype and allele frequencies in cases and controls werecompared using the chi square test and odds ratios (OR)and 95 confidence intervals (CI) were calculated by Fisherrsquosexact test (two-tailed) Patients were grouped based on theage of diagnosis (lt48 and gt48) tumor grade (grades I II IIIand IV) and hormone receptor status (ER+ERminus PR+PRminusand HER2+HER2minus) The genotype and allele frequencieswere calculated in each group and compared using SPSS 180for Windows A 119901 value of le005 was considered statisticallysignificant

3 Results

The age of the female patients suffering from breast cancerranged from 28 to 79 years and that of the normal controlranged from 28 to 68 years The age of diagnosis variedbut the majority were diagnosed above the age of 48 years

The ER PR and HER status were used to group the femalesas positive (+) or negative (minus) for the receptor and the resultsare presented in Table 3 The tumor grade was assessed andthemajority of the patients were in Grade II or III 27 patientswere triple negative and 40 were triple positive

The frequency of the genotypes and alleles of the threeSNPs was calculated in the total breast patients and controlgroups and the results are presented in Table 4 One of theSNPs showed association where the genotype and allele fre-quencies of rs1799794 (AgtG) showed a significant differencewhen the results in the patients and controls were compared

The genotype and allele frequencies of the three SNPsin breast cancer patients were also compared between thepatients grouped on the basis of age of diagnosis tumorgrade and ER PR and HER status The genotype and allelefrequencies of rs1799794 did not show any difference betweenthe ER+ERminus PR+PRminus and HER+HERminus patients patientswith different tumor grades and patients with different agesof diagnosis (results not shown) Most significant differenceswere seen in the frequency of rs1799796 in patients with dif-ferent age of diagnosis different tumor grades and differentER and HER2 status Only the results that were significantlydifferent are presented in Table 5 Between PR+ and PRminustherewere no significant differences in the genotype and allelefrequency of rs1799796 (results not presented)

Of the 143 breast cancer patients there were 27 (189)triple negative (ERminus PRminus and HER2minus) patients The geno-type frequencies of the three studied SNPs were calculatedin the triple negative group and compared to the resultsobtained in the normal control Genotype and allele fre-quencies of rs861539 and rs1799796 were not different in thepatients and control group however significant differenceswere seen in the frequencies of rs1799794 in the triple


Table 4 Genotype and allele frequencies of studied SNPs in breast cancer patients and controls

Cancer (total = 143) Control (total = 145) Breast cancer versus control119901 value

Number () Number () OR 95 CI 1205942

XRCC3Thr241Met rs861539 CgtT genotype frequencyCC 43 (3007) 32 (2207) RefCT 73 (5105) 78 (5379) 07 04ndash125 141 0236TT 27 (1889) 35 (2414) 059 03ndash116 235 0125CT+TT 100 (6993) 113 (7793) 067 04ndash115 211 0146CT+CC 116 (8111) 110 (7586) 135 08ndash239 111 0292

Alleles frequencyC 159 (5559) 142 (4897) RefT 127 (4441) 148 (5103) 077 06ndash108 229 01

XRCC3 rs1799794 AgtG genotype frequencyAA 102 (7133) 93 (6414) RefAG 40 (2797) 28 (193) 13 07ndash228 086 0353GG 1 (0007) 24 (1655) 003 0005ndash028 2077 lt00001AG+GG 41 (2867) 52 (3586) 072 044ndash118 17 0191AA+AG 142 (993) 121 (8344) 281 376ndash2112 2282 lt00001

Alleles frequencyA 244 (8533) 214 (7374) RefG 42 (1468) 76 (262) 048 032ndash074 1173 lt00001

XRCC3 rs1799796 AgtG genotype frequencyAA 59 (4126) 61 (4207) RefAG 53 (3706) 55 (3793) 099 059ndash167 000 0988GG 31 (2167) 29 (200) 110 059ndash205 010 0751AG+GG 84 (5874) 84 (579) 09 051ndash159 012 0726AA+AG 112 (7832) 116 (800) 103 065ndash165 002 0889

Alleles frequencyA 171 (5979) 177 (6103) RefG 115 (4021) 113 (3896) 105 075ndash147 009 076OR = odds ratio 95 CI = 95 confidence interval 1205942 = chi square SNP = single nucleotide polymorphism Ref reference

negative cancer patients and control group Only the resultsshowing significant differences are presented in Table 6

4 Discussion

It is well established that an individualrsquos capacity or risktoward developing cancer can be altered by genetic variationsin DNA repair genes [17] Polymorphisms that lead to proteinhaploinsufficiency are associated with an increased risk ofcancer development Studies conducted over the past decadehave identified such variations in a number of DNA repairgenes which are associated with either an increased suscepti-bility or an increased resistance to the development of cancersince they may modify DNA repair capacity These repairgenes have a pivotal role in maintaining genomic stabilitythrough different pathways and their correct functioning isimportant for genetic stability Among the many genes thathave been studied in recent yearsXRCC3has been implicatedas one of the candidates It contributes to important DNArepair mechanisms and plays a role in the repair of doublestrand breaks induced by a variety of external and internalfactors including ionizing radiation alkylating agents and

reactive oxygen species Studies in humans and mice withXRCC3 gene disruption confirm that these responses arelikely to contribute to cancer induction andor progression[18ndash20] It is emphasized that the study of such variationsmayhelp in understanding the aetiology of cancer

Studies in several populations have shown that XRCC3has several SNPs which exhibit polymorphism and that dif-ferent populations differ significantly in the genotype andallele frequencies of these SNPs [21] Studies conducted ondifferent types of cancer show several contradictory resultswhere some studies have shown an association between someSNPs inXRCC3 and a risk of colorectal cancer gastric cancerbreast cancer colorectal cancer lung cancer glioma andmeningioma liver cancer or head and neck cancer [3 22ndash29] while other studies have failed to show any association[30 31] Sliwinski et al [32] suggested that these polymor-phisms in the XRCC3 gene might be used as a predictivefactor of precancerous lesion for head and neck cancer ina Polish population In this respect a few studies related todifferent polymorphisms in XRCC3 and their interactionwith different cancers are listed in Table 6 which also showsseveral contradictory findings


Table 5 Comparison of the genotype and allele frequencies of the three SNPs in breast cancer patients grouped on the basis of age ofdiagnosis tumor grade and ER and HER status (only results that have a statistically significant difference between the compared groups areshown)

Grouping parameter Group SNP statisticsAge of diagnosisrs1799796 (AgtG)Genotype

lt48 yrsfrequency ()

gt48 yrsfrequency ()

OR CI 1205942

119901 value

AA 5139 3098 032 013ndash08 605 0014

AG 3333 4084 203 095ndash43 342 006

GG 1528 2818 306 12ndash76 605 0013

A 6806 5141 049 03ndash080 824 0005G 3194 4859 201

Tumour graders1799796 (AgtG)Genotype

II frequency () III frequency()

OR CI 1205942

119901 value

AA 3571 5682 566 147ndash218 729 0007

AG 4000 3636 057 025ndash13 177 018

GG 2429 682 017 005ndash068 729 0007

A 5571 7500 238 132ndash429 864 0003G 4429 2500 041

ER statusrs1799796 (AgtG)Genotype

ERminus frequency()

ER+ frequency()

OR CI 1205942

119901 value

AA 4375 3678 036 013ndash097 424 0039

AG 4170 3678 135 063ndash288 060 044

GG 1465 2644 277 103ndash745 424 004

A 6458 5517 056 034ndash094 496 0026G 3542 4483 177

HER statusrs1799796 (AgtG)Genotype

HERminusfrequency ()

HER+frequency ()

OR CI 1205942

119901 value

AA 4789 3380 029 011ndash075 691 0009

AG 3943 3534 126 059ndash271 037 0541

GG 1268 3088 345 13ndash88 691 0009

A 6761 5147 051 031ndash083 752 0006G 3239 4853 196OR = odds ratio 95 CI = 95 confidence interval 1205942 = chi square SNP = single nucleotide polymorphism

In this study on breast cancer patients and healthycontrols all the three studied SNPs exhibited polymorphismin the normal Saudi population and cancer patients All threegenotypes were identified for each SNP and the resultssuggested that some variations in XRCC3 may contributeto breast cancer susceptibility Significant association wasshown by rs1799794 anA toG transition in the 51015840UTRwherethemutantG allelewas highly protective against breast cancer(OR = 048 95 CI = 032ndash074 1205942 = 1173 119901 lt 00001)The protective effect was more obvious in the homozygotesfor the G allele (OR = 048 95 CI = 032ndash074 1205942 = 1173119901 lt 00001) This result is in agreement with several reportsthat have shown the G allele to be protective against lung

cancer and non-small-cell lung cancer inChinese [33 34] andesophageal and gastric cancer in Germans [35] and it wasrecently suggested that it may have a protective effect againstlate adverse effects induced by radiotherapy [36] In a reportfrom Jordan the G allele was shown to be associated withbreast cancer [37] while no association was reported fromthe UK population [2]

The rs1799794 also showed a significant association withthe triple negative cancer since the G allele was seen to besignificantly protective while the wild type A allele wassignificantly predisposing to breast cancer development inpatients who were triple negative Hence XRCC3 rs1799794AA is a potential predictive marker for triple negative breast


Table 6 Comparison of the genotype and allele frequencies of rs1799794 AgtG in triple negative patients compared to the health controlgroup

Triple negative cancer (total = 27) Control (total = 145) Breast cancer versus control119901 value



Alleles frequencyA 30 (5555) 214 (7374) RefG 24 (4444) 76 (262) 035 015ndash0855 57 0016OR = odds ratio 95 CI = 95 confidence interval 1205942 = chi square SNP = single nucleotide polymorphism

cancer in Saudi women and further investigations in otherpopulations are warranted for universal application in cancerdetection and prediction

We also evaluated rs1799794 as a predictive marker forearly disease onset disease severity and association with thehormone receptor (ER PR and HER2) status but no associ-ation was observed Hence it can be stated that rs1799794 isassociatedwith breast cancer and triple negative breast cancerin Saudis but not with disease onset or severity

No associationwas observed between rs861539 and breastcancer in Saudis This is a CgtT transition that results inthe substitution of Thr241Met and has been implicated as apotential predictivemarker for breast cancer in the Taiwanesepopulation [38] Among the Polish population this SNP hasbeen associated with cancer progression and grading It hasalso been shown to play a role in increasing risk of breastcancer in the British [2] and Taiwanese population [38] col-orectal cancer in Polish population [34] and breast and lungcancer in Taiwanese population [38 39] Several other studiesand meta-analyses have confirmed an association betweentheXRCC3Thr241Met polymorphism and it is suggested thatthis may be involved in modifying the risk of cancer [40]Interestingly some studies show that it may have a protectiveeffect [4 41] while still others failed to show any associationwith lung cancer in the Danish [42] breast cancer in thePolish [3] Belgian [43] and Jordanian populations [37]and ovarian cancer in a meta-analysis including CaucasianAsian and African populations [44] During our analysis nodifferences were found in the frequency of this SNPs whenthe patients were separated into groups on the basis of the ageof diagnosis tumor grade and receptor (ER PR and HER2)status Hence rs861539 cannot be considered as a predictivemarker for breast cancer in Saudis

Finally rs1799796 an AgtG transition in the XRCC3was studied and the genotypes and alleles failed to showany association with breast cancer in the Saudis Severalstudies have investigated this mutation in different cancersand the results are contradictory even in patients sufferingfrom the same type of cancer in different populations asshown inTable 7 A study from theBritish population showed

that rs1799796 decreases the risk of breast cancer [2] whileanother study from Belgium reported an increased riskassociated with this SNP in BRCA1 and BRCA2 carriers [43]More recently a significant association with ovarian cancerwas confirmed in ameta-analysis involvingCaucasian Asianand African populations [44] On the other hand studieson ovarian cancer from the British population [45] lungcancer in Danish population [42] bladder and breast cancerin American population [46 47] and prostate and urinarybladder cancer in Indians [30 48] failed to show any associa-tion with this SNP However when we grouped our cancerpatients on the bases of age of disease onset tumor gradeand hormone receptor (ER PR and HER2) status severalinteresting associationswere observedTheAallelewas foundto predispose to breast cancer at a younger age where thepatients diagnosed at age lt48 years had a significantly higherfrequency compared to those who developed cancer at an agelater than 48 yearsTheA allele also occurred at a significantlyhigher frequency in patients suffering from tumor grade IIIcompared to tumor grade II suggesting its involvement indisease severity It also occurred at a significantly higherfrequency in ERminus andHER2minus females compared to their ER+and HER2+ counterparts Hence we suggest that rs1799796may be considered as a disease severity marker

In conclusion it is obvious that populations differ in thegenotype and allele frequencies of different SNPs and alsodiffer in the extent and nature of association of a genotypeor allele with disease development Association studies playan important role in identification of genetic markers thatmay help in presymptomatic diagnosis of a disease stateincluding cancer In addition therapeutic measure may bedirected towards those SNPs that influence gene expressionof the respected gene One drawback of such studies is thatthe frequencies of the SNP alleles show significant differencesbetween different populations even in the control groupshencemaking it mandatory that studies of this nature need tobe performed for each individual population in an attemptto identify ldquopopulation specific markersrdquo In addition suchstudies will contribute towards the development of the fieldof ldquopersonalized medicinerdquo with individualized treatmentstrategies


Table 7 Association studies of rs1799794 (AG) rs861539 (CT) and rs1799796 (AG) in XRCC3 in different types of cancer and in differentpopulations

Cancer types Effect Number Population Refrs1799794 (AG) association of G allele

Breast cancer Protective 143 Saudis lowast

Esophageal and gastric Survival 258 Germans [35]Lung cancer Decreased risk in carriers of G allele mdash Chinese [33]Breast cancer risk Modified in patients carrying BRCA1 BRCA2 mutation mdash Belgian [43]Prostate cancer Gastrointestinal toxicity 698 Spanish [49]Non-small-cell lung Protective effect of G allele 507 Chinese [34]Breast cancer No association British [2]Ovarian cancer Association mdash Meta-analysis [44]Breast cancer Association mdash Jordanian [37]

rs861539 (CT) association of T alleleBreast cancer No association 143 Saudis lowast

Colorectal cancer Increased risk (association) 100 Polish [34]Breast cancer Increased risk (association) 1826 British [2]Bladder cancer Protective role 214 Italian [41]Colorectal cancer Protective role 128 British [4]Lung cancer No association 272 Danish [42]Breast cancer No association Association with cancer progression and grading 700 Polish [3]Breast cancer Association Taiwanese [38]Breast cancer No association Jordanian [37]

rs1799796 (AG) association of G alleleBreast cancer No association 143 Saudi lowast

Bladder cancer No association 696 American [46]Oral premalignant lesions Strong association (increases risk) 147 American [50]Prostate cancer No association 192 Indian [48]Urinary bladder cancer No association 211 Indian [30]Breast cancer Increases risk in BRCA1 BRCA2 mdash Belgian [43]Breast cancer Decreased risk 2205 British [2]Breast cancer No association 1004 American [47]Lung cancer No association 265 Danish [42]Ovarian cancer No association 1600 British [45]Ovarian cancer Association Meta-analysis [44]lowast = this study

Conflict of Interests

The authors declare that they do not have any competinginterests with any group

Acknowledgment

This project was financially supported by King Saud Univer-sity Vice Deanship of Research Chairs

References

[1] E Synowiec J Stefanska Z Morawiec J Blasiak and K Woz-niak ldquoAssociation between DNA damage DNA repair genesvariability and clinical characteristics in breast cancer patientsrdquoMutation Research Fundamental and Molecular Mechanisms ofMutagenesis vol 648 no 1-2 pp 65ndash72 2008

[2] B Kuschel A Auranen S McBride et al ldquoVariants in DNAdouble-strand break repair genes and breast cancer susceptibil-ityrdquo Search Results HumanMolecular Genetics vol 11 no 12 pp1399ndash1407 2002

[3] H Romanowicz-Makowska B Smolarz M Zadrozny et alldquoSingle nucleotide polymorphisms in the homologous recom-bination repair genes and breast cancer risk in Polish womenrdquoTheTohoku Journal of ExperimentalMedicine vol 224 no 3 pp201ndash208 2011

[4] RMort LMo CMcEwan andDWMelton ldquoLack of involve-ment of nucleotide excision repair gene polymorphisms incolorectal cancerrdquo British Journal of Cancer vol 89 no 2 pp333ndash337 2003

[5] X-F He W Wei J Su et al ldquoAssociation between the XRCC3polymorphisms and breast cancer risk meta-analysis based oncase-control studiesrdquo Molecular Biology Reports vol 39 no 5pp 5125ndash5134 2012


[6] R B Setlow ldquoDNA repair pathwaysrdquo inDNA Repair andMuta-genesis in Eukaryotes WM Generoso M D Shalby and F J deSerresi Eds vol 15 of Basic Life Sciences chapter 3 pp 45ndash54Plenum Press New York NY USA 1980

[7] C Richardson ldquoRAD51 genomic stability and tumorigenesisrdquoCancer Letters vol 218 no 2 pp 127ndash139 2005

[8] N Liu J E Lamerdin R S Tebbs et al ldquoXRCC2 and XRCC3new human Rad51-family members promote chromosome sta-bility and protect against DNA cross-links and other damagesrdquoMolecular Cell vol 1 no 6 pp 783ndash793 1998

[9] M Garcıa-Closas K M Egan P A Newcomb et al ldquoPolymor-phisms in DNA double-strand break repair genes and risk ofbreast cancer twopopulation-based studies inUSAandPolandand meta-analysesrdquo Human Genetics vol 119 no 4 pp 376ndash388 2006

[10] N R Jacobsen B A Nexoslash A Olsen et al ldquoNo associationbetween the DNA repair gene XRCC3 T241M polymorphismand risk of skin cancer and breast cancerrdquo Cancer EpidemiologyBiomarkers and Prevention vol 12 no 6 pp 584ndash585 2003

[11] B Thyagarajan K E Anderson A R Folsom et al ldquoNoassociation between XRCC1 and XRCC3 gene polymorphismsand breast cancer risk Iowa Womenrsquos Health studyrdquo CancerDetection and Prevention vol 30 no 4 pp 313ndash321 2006

[12] S-A Lee K-M Lee S K Park et al ldquoGenetic polymorphism ofXRCC3Thr241Met and breast cancer risk case-control study inKorean women and meta-analysis of 12 studiesrdquo Breast CancerResearch and Treatment vol 103 no 1 pp 71ndash76 2007

[13] S Han H-T Zhang Z Wang et al ldquoDNA repair gene XRCC3polymorphisms and cancer risk a meta-analysis of 48 case-control studiesrdquo European Journal of Human Genetics vol 14no 10 pp 1136ndash1144 2006

[14] M Manuguerra F Saletta M R Karagas et al ldquoXRCC3 andXPDERCC2 single nucleotide polymorphisms and the risk ofcancer a HuGE reviewrdquo American Journal of Epidemiology vol164 no 4 pp 297ndash302 2006

[15] K P Economopoulos and T N Sergentanis ldquoXRCC3Thr241Met polymorphism and breast cancer risk a meta-analysisrdquo Breast Cancer Research and Treatment vol 121 no 2pp 439ndash443 2010

[16] National Cancer RegistryCancer Incidence Report Saudi Arabia2002 National Cancer Registry Riyadh Saudi Arabia 2007

[17] J Han C Haiman T Niu et al ldquoGenetic variation in DNArepair pathway genes and premenopausal breast cancer riskrdquoBreast Cancer Research and Treatment vol 115 no 3 pp 613ndash622 2009

[18] M Z Zdzienicka ldquoMammalian mutants defective in theresponse to ionizing radiation-induced DNA damagerdquo Muta-tion ResearchDNA Repair vol 336 no 3 pp 203ndash213 1995

[19] M Z Zdzienicka ldquoMammalian X-ray-sensitive mutants whichare defective in non-homologous (illegitimate) DNA double-strand break repairrdquo Biochimie vol 81 no 1-2 pp 107ndash116 1999

[20] J Thacker and M Z Zdzienicka ldquoThe XRCC genes expandingroles in DNA double-strand break repairrdquo DNA Repair vol 3no 8-9 pp 1081ndash1090 2004

[21] M Alanazi A A K Pathan S A Ajaj et al ldquoDna repair genesXRCC1 XRCC3 XPD ANDOGG1 polymorphisms among thecentral region population of Saudi Arabiardquo Biological Researchvol 46 no 2 pp 161ndash167 2013

[22] B Smolarz M Makowska D Samulak et al ldquoAssociationbetween single nucleotide polymorphisms (SNPs) of XRCC2

andXRCC3homologous recombination repair genes and triple-negative breast cancer in Polish womenrdquo Clinical and Experi-mental Medicine vol 15 no 2 pp 151ndash157 2014

[23] I Gok M Baday S Cetinkunar K Kilic and B C Bilgin ldquoPol-ymorphisms in DNA repair genes XRCC2 and XRCC3 riskof gastric cancer in Turkeyrdquo Bosnian Journal of Basic MedicalSciences vol 14 no 4 pp 214ndash218 2014

[24] K-Q Luo S-Q Mu Z-X Wu Y-N Shi and J-C Peng ldquoPol-ymorphisms in DNA repair genes and risk of glioma andmeningiomardquo Asian Pacific Journal of Cancer Prevention vol14 no 1 pp 449ndash452 2013

[25] SNissar A S Sameer TA LoneNAChowdri andR RasoolldquoXRCC3 Thr241Met gene polymorphism and risk of colorectalcancer in Kashmir a case control studyrdquo Asian Pacific Journalof Cancer Prevention vol 15 no 22 pp 9621ndash9625 2014

[26] S Guo X Li M Gao Y Li B Song and W Niu ldquoThe rela-tionship between XRCC1 andXRCC3 gene polymorphisms andlung cancer risk in northeastern Chineserdquo PLoS ONE vol 8 no2 Article ID e56213 2013

[27] BMucha K Przybylowska-Sygut A J Dziki L Dziki A Sygutand I Majsterek ldquoAssociation of THR241MET polymorphismof XRCC3 gene with risk of colorectal cancer in the polishpopulationrdquo Polish Journal of Pathology vol 64 no 3 pp 185ndash190 2013

[28] R Krupa J Kasznicki M Gajecka et al ldquoPolymorphisms of theDNA repair genes XRCC1 and ERCC4 are not associated withsmoking- and drinking-dependent larynx cancer in a Polishpopulationrdquo Experimental Oncology vol 33 no 1 pp 55ndash562011

[29] L Zhang Z Zhang and W Yan ldquoSingle nucleotide polymor-phisms for DNA repair genes in breast cancer patientsrdquo ClinicaChimica Acta vol 359 no 1-2 pp 150ndash155 2005

[30] R D Mittal R Gangwar R K Mandal P Srivastava and D KAhirwar ldquoGene variants of XRCC4 and XRCC3 and their asso-ciation with risk for urothelial bladder cancerrdquo Molecular Biol-ogy Reports vol 39 no 2 pp 1667ndash1675 2012

[31] P Ding Y Yang L Cheng et al ldquoThe relationship betweenseven commonpolymorphisms fromfiveDNArepair genes andthe risk for breast cancer in Northern Chinese womenrdquo PLoSONE vol 9 no 3 Article ID e92083 2014

[32] T Sliwinski A Walczak K Przybylowska et al ldquoPolymor-phisms of the XRCC3 C722T and the RAD51 G135C genesand the risk of head and neck cancer in a Polish populationrdquoExperimental and Molecular Pathology vol 89 no 3 pp 358ndash366 2010

[33] M Huang X Chen Y Qiu L Fan J Chen and L Cai ldquoRela-tionship between XRCC3 gene polymorphisms and lung can-cerrdquoWei Sheng Yan Jiu vol 40 no 2 pp 187ndash190 2011

[34] F He S-C Chang G M Wallar Z-F Zhang and L CaildquoAssociation of XRCC3 and XRCC4 gene polymorphismsfamily history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population a case-control studyrdquoJournal of Human Genetics vol 58 no 10 pp 679ndash685 2013

[35] K Ott P S Rachakonda B Panzram et al ldquoDNA repair geneand MTHFR gene polymorphisms as prognostic markers inlocally advanced adenocarcinoma of the esophagus or stomachtreated with cisplatin and 5-fluorouracil-based neoadjuvantchemotherapyrdquo Annals of Surgical Oncology vol 18 no 9 pp2688ndash2698 2011

[36] Y-Z Song F-J Han M Liu C-C Xia W-Y Shi and L-HDong ldquoAssociation between single nucleotide polymorphisms


in XRCC3 and radiation-induced adverse effects on normaltissue a meta-analysisrdquo PLoS ONE vol 10 no 6 Article IDe0130388 2015

[37] M S Al Zoubi ldquoX-ray repair cross-complementing protein 1and 3 polymorphisms and susceptibility of breast cancer in aJordanian populationrdquo SaudiMedical Journal vol 36 no 10 pp1163ndash1167 2015

[38] C H Su W S Chang P S Hu et al ldquoContribution of DNAdouble-strand break repair gene XRCC3 genotypes to triple-negative breast cancer riskrdquo Cancer Genomics Proteomics vol12 no 6 pp 359ndash367 2015

[39] H J Chen W S Chang T C Hsia et al ldquoContribution ofgenotype of DNA double-strand break repair gene XRCC3gender and smoking behavior to lung cancer risk in TaiwanrdquoAnticancer Research vol 35 no 7 pp 3893ndash3899 2015

[40] Z Wang and W Zhang ldquoAssociation between XRCC3Thr241Met polymorphism and colorectal cancer riskrdquo TumorBiology vol 34 no 3 pp 1421ndash1429 2013

[41] M Shen R J Hung P Brennan et al ldquoPolymorphisms of theDNA repair genes XRCC1 XRCC3 XPD interaction with envi-ronmental exposures and bladder cancer risk in a case-controlstudy in northern Italyrdquo Cancer Epidemiology Biomarkers andPrevention vol 12 no 11 part 1 pp 1234ndash1240 2003

[42] N R Jacobsen O Raaschou-Nielsen B Nexoslash et al ldquoXRCC3Polymorphisms and risk of lung cancerrdquoCancer Letters vol 213no 1 pp 67ndash72 2004

[43] A Vral P Willems K Claes et al ldquoCombined effect of pol-ymorphisms in Rad51 and XRCC3 on breast cancer risk andchromosomal radiosensitivityrdquoMolecularMedicine Reports vol4 no 5 pp 901ndash912 2011

[44] C Yuan X Liu S Yan C Wang and B Kong ldquoAnalyzingassociation of the XRCC3 gene polymorphism with ovariancancer riskrdquo BioMed Research International vol 2014 ArticleID 648137 9 pages 2014

[45] A Auranen H Song C Waterfall et al ldquoPolymorphisms inDNA repair genes and epithelial ovarian cancer riskrdquo Interna-tional Journal of Cancer vol 117 no 4 pp 611ndash618 2005

[46] X Wu J Gu H B Grossman et al ldquoBladder cancer predis-position a multigenic approach to DNA-repair and cell-cycle-control genesrdquoAmerican Journal of HumanGenetics vol 78 no3 pp 464ndash479 2006

[47] J Han S E Hankinson H Ranu I De Vivo and D J HunterldquoPolymorphisms in DNA double-strand break repair genes andbreast cancer risk in the Nursesrsquo Health studyrdquo Carcinogenesisvol 25 no 2 pp 189ndash195 2004

[48] R K Mandal R Kapoor and R D Mittal ldquoPolymorphic var-iants of DNA repair gene XRCC3 and XRCC7 and risk of pros-tate cancer a study from North Indian populationrdquo DNA andCell Biology vol 29 no 11 pp 669ndash674 2010

[49] L Fachal A Gomez-Caamano P Peleteiro et al ldquoAssociation ofa XRCC3 polymorphism and rectummean dose with the risk ofacute radio-induced gastrointestinal toxicity in prostate cancerpatientsrdquo Radiotherapy and Oncology vol 105 no 3 pp 321ndash328 2012

[50] H Yang S M Lippman M Huang et al ldquoGenetic polymor-phisms in double-strand break DNA repair genes associatedwith risk of oral premalignant lesionsrdquo European Journal ofCancer vol 44 no 11 pp 1603ndash1611 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Table 1 Primers used for amplification of SNPs in XRCC3

SNPs in XRCC3 Primers

Thr241Met c722 (rs861539) F 51015840-GCTGTCTCGGGGCATGGCTC-31015840

R 31015840-TTTAGCCAGGATGCGGAAGC-51015840

c316 (rs1799794) F 51015840-TGAGGCGCCTAATCAGC-31015840

R 31015840-CGCTGCTTGACACAGTCCA-51015840

c562-14 (rs1799796) F 51015840-GACACCTCTACAGAGGACG-31015840

R 31015840-CTGTGCCTAACCATCGAGAA-51015840

XRCC3 is one of the protein components involved in theHRR pathway and Liu et al [8] showed that XRCC3 interactsdirectlywithRAD51 andmay cooperatewith it during recom-binational repair mechanisms Several polymorphisms havebeen identified in this gene where some of the resultinggenetic variants may alter the capacity of DNA repairmechanism and hence may be associated with increased ordecreased susceptibility to tumor genesis [9] Genetic poly-morphisms inHRR genes that can lead to protein haploinsuf-ficiency are generally associated with increased cancer riskThough theXRCC3 gene is a highly suspected candidate genefor cancer susceptibility several association studies on theXRCC3 polymorphisms in cancer have reported conflictingresults [10]

The previous published data on the association betweenXRCC3 Thr241Met A4541G and A17893G polymorphismsand breast cancer risk remains largely controversial andpopulation related differences in association are reported fre-quently Kuschel et al [2] performed genetic association stud-ies in a population-based breast cancer case-control studyand analyzed polymorphisms in 7 genes involved in DNArepair Genotype frequencies differed between cases andcontrols for 2 polymorphisms in the XRCC3 gene Howevermost subsequent studies on Caucasians failed to confirm thisassociation [10 11] though a few studies did report thatXRCC3 Thr241Met is related to an increased risk of breastcancer Several meta-analyses using pooled data were per-formed and some showed a small but significant increase incancer risk [12ndash15]

In Saudi Arabia as in several other countries of the worldbreast cancer is the most common cancer in females [16]Though the incidence of breast cancer is lower than in West-ern countries it ranks highest amongst all the malignanciesseen among Saudi females [16] Interest in the moleculargenetics of cancer among Saudis has gained momentum overthe last few years and differentDNA repair genes are the focusof several studies With this background we initiated thiscase-control study on Saudi breast cancer patients and inves-tigated three commonly reported XRCC3 polymorphisms(Thr241Met c722 (rs861539) c562-14 (rs1799796) and c316(rs1799794)) in the patients in comparison with the healthycontrols

2 Material and Methods

21 Study Population This study was approved by the Insti-tutional Review Board (IRB) of King Fahad Hospital (KFH)

Written informed consent was obtained from all participantsThis was conducted as a case-control study involving 143females (median age = 513 plusmn 10 yrs) suffering from breastcancer and 145 age matched normal healthy controls allof Saudi Arabian ethnicity The breast cancer patients wereattending the outpatient clinics of the clinical coinvestigators(KFH) in Riyadh Saudi Arabia and the controls were alsoattending KFH for minor illnesses They were recruitedfollowing physical examinations after diagnostic exclusionof cancer or history of cancer and cancer-related diseasesDemographic data age at diagnosis tumor grade and recep-tor status of estrogen receptor (ER) progesterone receptor(PR) and human epidermal growth factor receptor 2 (HER2)were recorded

22 DNA Extraction Approximately 3mL blood sampleswere collected by venepuncture in ethylene diamine tetraacetic acid (EDTA) containing vacutainer tubes from allsubjects enrolled in the study DNA (genomic) was extractedfrom blood samples using a QIAamp DNA blood mini kit(Qiagen Valencia CA USA) following the manufacturerrsquosinstructionsThe extracted DNAwas spectrophotometricallyquantitated using NanoDrop 8000 (Thermo Scientific USA)and purity was determined using the standard A260A280and A260A230 ratios

23 Genotyping Three SNPs in XRCC3 were genotypedusing PCR-RFLPThe fragment of interest was amplified withthe PCR primers listed in Table 1

For the PCR 25 120583L PCRmixture was prepared and it con-tained 20 ng of DNA 10 pmol of each primer 02mmolL ofdNTPs 2mmolL ofMgCl

2 and 1U of TaqDNApolymerase

Thermal cycling conditions used during this study consistedof an initial denaturation step at 95∘C for 10min followedby 35 cycles of 95∘C for 45 sec 60∘C for 50 sec and 72∘Cfor 45 sec and a final step at 72∘C for 10 minutes All PCRproducts were subjected to electrophoresis and stored at 4∘Cuntil required for further analysisThe fragment size obtainedusing each primer set is presented in Table 2 The fragmentsobtained were treated with the specific restriction endonu-clease that is FokI for rs1799794 PvuII for rs1799796 andNlaIII for rs861539 The concentrations of each enzyme usedwere as follows 1 U of the enzyme FokI with BSA (1120583L) and5 120583L PCR products 05 120583L NlaIII with 05120583L BSA and 1 120583Lbuffer 4 used with 5120583L PCR product and 02 120583L PvuII and1 120583L of buffer X2 NEB with 5 120583L of the PCR product For FokIand NlaIII digestion conditions were as follows incubation



XRCC3 SNPPCR

product size(bp)


RE treatment


CT 231 107 112 amp 12 bpTT 112 107 amp 12 bp


AG 100 193 amp 293 bpGG 293 bp


AG 283 367 amp 650 bpGG 283 amp 376 bp



Averageage (years)






I = 18II = 71III = 45IV = 9







3 Results

















4 Discussion









OR CI 1205942

119901 value

AA 5139 3098 032 013ndash08 605 0014

AG 3333 4084 203 095ndash43 342 006

GG 1528 2818 306 12ndash76 605 0013

A 6806 5141 049 03ndash080 824 0005G 3194 4859 201



OR CI 1205942

119901 value

AA 3571 5682 566 147ndash218 729 0007

AG 4000 3636 057 025ndash13 177 018

GG 2429 682 017 005ndash068 729 0007

A 5571 7500 238 132ndash429 864 0003G 4429 2500 041


ERminus frequency()

ER+ frequency()

OR CI 1205942

119901 value

AA 4375 3678 036 013ndash097 424 0039

AG 4170 3678 135 063ndash288 060 044

GG 1465 2644 277 103ndash745 424 004

A 6458 5517 056 034ndash094 496 0026G 3542 4483 177



HER+frequency ()

OR CI 1205942

119901 value

AA 4789 3380 029 011ndash075 691 0009

AG 3943 3534 126 059ndash271 037 0541

GG 1268 3088 345 13ndash88 691 0009




























Acknowledgment


References






























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



XRCC3 SNPPCR

product size(bp)


RE treatment


CT 231 107 112 amp 12 bpTT 112 107 amp 12 bp


AG 100 193 amp 293 bpGG 293 bp


AG 283 367 amp 650 bpGG 283 amp 376 bp



Averageage (years)






I = 18II = 71III = 45IV = 9







3 Results

















4 Discussion









OR CI 1205942

119901 value

AA 5139 3098 032 013ndash08 605 0014

AG 3333 4084 203 095ndash43 342 006

GG 1528 2818 306 12ndash76 605 0013

A 6806 5141 049 03ndash080 824 0005G 3194 4859 201



OR CI 1205942

119901 value

AA 3571 5682 566 147ndash218 729 0007

AG 4000 3636 057 025ndash13 177 018

GG 2429 682 017 005ndash068 729 0007

A 5571 7500 238 132ndash429 864 0003G 4429 2500 041


ERminus frequency()

ER+ frequency()

OR CI 1205942

119901 value

AA 4375 3678 036 013ndash097 424 0039

AG 4170 3678 135 063ndash288 060 044

GG 1465 2644 277 103ndash745 424 004

A 6458 5517 056 034ndash094 496 0026G 3542 4483 177



HER+frequency ()

OR CI 1205942

119901 value

AA 4789 3380 029 011ndash075 691 0009

AG 3943 3534 126 059ndash271 037 0541

GG 1268 3088 345 13ndash88 691 0009




























Acknowledgment


References






























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












4 Discussion









OR CI 1205942

119901 value

AA 5139 3098 032 013ndash08 605 0014

AG 3333 4084 203 095ndash43 342 006

GG 1528 2818 306 12ndash76 605 0013

A 6806 5141 049 03ndash080 824 0005G 3194 4859 201



OR CI 1205942

119901 value

AA 3571 5682 566 147ndash218 729 0007

AG 4000 3636 057 025ndash13 177 018

GG 2429 682 017 005ndash068 729 0007

A 5571 7500 238 132ndash429 864 0003G 4429 2500 041


ERminus frequency()

ER+ frequency()

OR CI 1205942

119901 value

AA 4375 3678 036 013ndash097 424 0039

AG 4170 3678 135 063ndash288 060 044

GG 1465 2644 277 103ndash745 424 004

A 6458 5517 056 034ndash094 496 0026G 3542 4483 177



HER+frequency ()

OR CI 1205942

119901 value

AA 4789 3380 029 011ndash075 691 0009

AG 3943 3534 126 059ndash271 037 0541

GG 1268 3088 345 13ndash88 691 0009




























Acknowledgment


References






























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






OR CI 1205942

119901 value

AA 5139 3098 032 013ndash08 605 0014

AG 3333 4084 203 095ndash43 342 006

GG 1528 2818 306 12ndash76 605 0013

A 6806 5141 049 03ndash080 824 0005G 3194 4859 201



OR CI 1205942

119901 value

AA 3571 5682 566 147ndash218 729 0007

AG 4000 3636 057 025ndash13 177 018

GG 2429 682 017 005ndash068 729 0007

A 5571 7500 238 132ndash429 864 0003G 4429 2500 041


ERminus frequency()

ER+ frequency()

OR CI 1205942

119901 value

AA 4375 3678 036 013ndash097 424 0039

AG 4170 3678 135 063ndash288 060 044

GG 1465 2644 277 103ndash745 424 004

A 6458 5517 056 034ndash094 496 0026G 3542 4483 177



HER+frequency ()

OR CI 1205942

119901 value

AA 4789 3380 029 011ndash075 691 0009

AG 3943 3534 126 059ndash271 037 0541

GG 1268 3088 345 13ndash88 691 0009




























Acknowledgment


References






























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
























Acknowledgment


References






























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

research article polymorphisms in dna repair gene xrcc3 and … · 2019. 7. 30. · susceptibility...

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