The Correlation Between TNF-α Promoter Gene Polymorphism and Genetic Susceptibility to Cervical Cancer.
Journal: 2018/November - Technology in Cancer Research and Treatment
ISSN: 1533-0338
Abstract:
To investigate the association between the susceptibility to cervical cancer and the single nucleotide polymorphisms of 5 tumor necrosis factor-α promoter genes (rs361525, rs1800629, rs1800750, rs1799964, and rs673) in Chinese women. A total of 946 peripheral blood samples were collected from women of Han Ethnicity in Shandong province. Of them, 452 were diagnosed with cervical squamous cell carcinomas. The study also included a control group of 494 healthy women. The targeted single nucleotide polymorphisms were analyzed by TaqMan probe method. (1) The rate of high-risk subtype human papillomavirus infection in exfoliated cervical epithelial cells was significantly higher in patients with cervical cancer than the control group (91.4% vs 10.3%, P < .01). The rate of human papillomavirus infection was lower in patients with carcinoma in situ than those with invasive carcinoma (77.9% vs 95.4%, P < .01). (2) There was a significant difference for rs361525 genotype (CC/CT/TT) between the control, carcinoma in situ, and invasive carcinoma groups ( P < .001). Both rs1800629 and rs1799964 genotypes (both GG/GA/AA) were also different between these groups ( P < .001 and P < .001). (3) The allele frequencies of rs361525, rs1800629, and rs1799964 were significantly correlated with the diagnosis of cervical cancer. The frequency of T allele in rs361525 was significantly higher for cervical cancer group (10.8%) than control group (3.8%; odds ratio = 3.04, 95% confidence interval = 1.76-5.25, P < .01). The frequency of A allele in rs1800629 was significantly higher for cervical cancer (29.9%) than control group (14.2%; odds ratio = 2.58, 95% confidence interval = 1.87-3.56, P < .01). The frequency of A allele in rs1799964 was also higher for cervical cancer group (38.3%) than control group (16.4%; odds ratio = 1.43, 95% confidence interval = 1.07-1.91, P < .05). The rs361525, rs1800629, and rs17999645 were significantly correlated with the diagnosis of cervical cancer.
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Technology in Cancer Research & Treatment. Dec/31/2017; 17
Published online Jun/25/2018

The Correlation Between TNF-α Promoter Gene Polymorphism and GeneticSusceptibility to Cervical Cancer

Abstract

To investigate the association between the susceptibility to cervical cancer and thesingle nucleotide polymorphisms of 5 tumor necrosis factor-α promoter genes (rs361525,rs1800629, rs1800750, rs1799964, and rs673) in Chinese women. A total of 946 peripheralblood samples were collected from women of Han Ethnicity in Shandong province. Of them,452 were diagnosed with cervical squamous cell carcinomas. The study also included acontrol group of 494 healthy women. The targeted single nucleotide polymorphisms wereanalyzed by TaqMan probe method. (1) The rate of high-risk subtype human papillomavirusinfection in exfoliated cervical epithelial cells was significantly higher in patientswith cervical cancer than the control group (91.4% vs 10.3%, P < .01).The rate of human papillomavirus infection was lower in patients with carcinoma in situthan those with invasive carcinoma (77.9% vs 95.4%, P < .01). (2)There was a significant difference for rs361525 genotype (CC/CT/TT) between the control,carcinoma in situ, and invasive carcinoma groups (P < .001). Bothrs1800629 and rs1799964 genotypes (both GG/GA/AA) were also different between these groups(P < .001 and P < .001). (3) The allelefrequencies of rs361525, rs1800629, and rs1799964 were significantly correlated with thediagnosis of cervical cancer. The frequency of T allele in rs361525 was significantlyhigher for cervical cancer group (10.8%) than control group (3.8%; odds ratio = 3.04, 95%confidence interval = 1.76-5.25, P < .01). The frequency of A allelein rs1800629 was significantly higher for cervical cancer (29.9%) than control group(14.2%; odds ratio = 2.58, 95% confidence interval = 1.87-3.56, P <.01). The frequency of A allele in rs1799964 was also higher for cervical cancer group(38.3%) than control group (16.4%; odds ratio = 1.43, 95% confidence interval = 1.07-1.91,P < .05). The rs361525, rs1800629, and rs17999645 were significantlycorrelated with the diagnosis of cervical cancer.

Introduction

China’s National Health and Family Planning Commission estimates that in China every yearapproximately 132 000 new cases of cervical cancer are diagnosed, and 30 000 deaths are dueto cervical cancer.1 Worldwide, cervical cancer is also the fourth most common type of malignancy in womenand the second most common type of cancer in developing countries.2 Studies have proved that human papillomavirus (HPV) infection and cervical cancer areclosely related, with more than 95% of patients with cervical cancer being positive onhigh-risk HPV subtype infection.36 While the pathogenesis of cervical cancer has not yet been fully elucidated, itsoccurrence involves a multifactorial, multistep complex process.79 Although nearly 30% of sexually active women were infected with HPV shortly aftertheir first sexual intercourse, most of them were able to clear HPV infection throughautonomous cellular immunity when they were young.10 Only a small number of patients with persistent infection develop cervical cancer.Studies have shown that gene-based genetic polymorphisms of individual immune response wereclosely related to the risk of cervical cancer.1113 Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine produced by monocytesand macrophages and plays an important role in promoting inflammatory response, cellproliferation, and inducing apoptosis. Tumor necrosis factor-α is a polypeptide thatdirectly kills or inhibits tumor cells and plays an important role in the development andprogression of tumors and is the most important proinflammatory cytokine.14,15

Single nucleotide polymorphisms (SNPs) refer to DNA sequence polymorphisms at the genomiclevel due to the presence of a single nucleotide switch (or transversion).16 By comparing the genotype frequency of the SNP locus and allele frequency between thenormal control and the patients, the association between a locus gene and the risk of adisease can be explored.17 In studies of SNPs of TNF-α gene promoter, rs361525 (−238) and rs1800629 (−308) weremost frequently investigated. Polymorphism of rs1800629 (−308) has been shown to be a riskfactor for a variety of cancers, such as breast cancer, gastric cancer, and liver cancer.1820 The rs361525 (−238) locus is located on a 25-base pair repressor gene,21 and its SNP has been shown to be associated with the protection against cancer.22,23 In addition, the relationship between SNP of rs1800629 (−308) and cervical cancer hasbeen studied in various racial populations, including Spanish, Mexican, and Indian, and Aallele was associated with an increased risk of cervical cancer2427 as confirmed by a meta-analysis.23 Although a large number of epidemiological studies of TNF-α gene SNPs have beenconducted to investigate their relationship with the patients’ susceptibility to cervicalcancer, the results are inconsistent, and significant racial differences may also exist.Furthermore, there are also conflicting results on the association between rs361525 (−238)polymorphism and cervical cancer risk.28,29

Our team has previously (2015) reported the findings of detecting the SNP of the TNF-α gene−857 locus (rs1799724) using TaqMan SNP Genotyping assay. The results showed that SNP ofthis locus was significantly correlated with cervical cancer. The frequency of T allele atthe TNF-α gene −857 was markedly higher in cervical cancer group than that in control group.The TT+AT genotype was associated with the risk of cervical cancer, while CC genotype was not.30 Studies have shown that the polymorphism of TNF-α promoter region on chromosome 6 isalso closely related to the susceptibility to cervical cancer.31,32 In many studies of SNPs of TNF-α promoter gene, the data from the Asian populationare relatively scarce, especially in the Chinese women.

Based on the findings of previous study, 5 SNP loci from the candidate genes for TNF-αpromoter that may be associated with genetic susceptibility to cervical cancer rs361525(−238), rs1800629 (−308), rs1800750 (−376), rs1799964 (−1031), and rs673 (−244) wereselected to study their genotype and allele frequency distribution. The correlation betweenthese 5 SNP loci and cervical cancer in Chinese women has not been reported.

Materials and Methods

A total of 946 female participants were enrolled, and their peripheral blood samples werecollected. All of them were of Han ethnicity and lived in Shandong province in China. Thecases were consecutively enrolled from a single large medical center.

Study Population

Cervical cancer group

The inclusion criteria were patients with pathologically confirmed cervical squamouscell carcinoma; no other history of malignancy did not undergo radiation and/orchemotherapy. A total of 452 cases (including 104 cases of carcinoma in situ and 348cases of invasive cervical carcinoma) were enrolled from January 2011 to October 2015.All of them were married, aged from 27.7 to 67.0 years (mean 47.0 ± 14.5 years). Thesurvey questionnaire was adopted from the United States Seattle Hospital Cervical CancerEpidemiologic study.33 Investigators conducted the interview after obtaining informed consent.Epidemiological survey included demographics, occupational exposure history, familyhistory of cancer, smoking history, sexual behavior, pregnancy and delivery history, andso on.

Healthy control group

Control participants were healthy and married women randomly selected from the samearea during the study period. They were matched with the cases by age and geographiclocation. A total of 494 control participants were enrolled, aged from 26.0 to 69.0years, with an average age of 47.0 ± 15.5 years. This study was approved by theInstitutional Ethics Committee prior to initiation (No. 2013ZX05).

Genetic Polymorphism Testing

For specific SNP loci, real-time quantitative polymerase chain reaction (PCR) usingTaqMan probe method was performed for the detection and analysis of polymorphism.

DNA extraction from peripheral blood lymphocytes

Peripheral venous blood (4-5 mL) was collected from each participant using EDTAanticoagulated tube and stored at −70°C. DNA extraction kit (Beijing TiangenBiotechnology Company, Bejing, China) was used to extract DNA from peripheral bloodlymphocytes according to the manufacture instruction.

Experimental materials and equipment

TaqMan SNP genotyping probes for SNP loci rs361525, rs1800629, rs1800750, rs1799964,and rs673 were provided by Shanghai Keikang Biotechnology Co, Ltd (Table 1). Master MIX and AppliedBiosystems 7900HT Fast Real-Time PCR System were manufactured by ABI Genes (AppliedBiosystems, USA). The 384-well PCR plate was purchased from Roche, Germany.

Table 1.
TaqMan Probes and Sequences.
SNP SiteItemsSequence
rs361525Forward primerCTCGGTTTCTTCTCCATCGC
Reverse primerCAGCCTCCAGGGTCCTACAC
Wild probeTET-TCCCCATCCTCCCTGCTCtG ATT-BHQ
Mutation probeFAM-CCCATCCTCCCTGCTCcG ATT-BHQ
rs1800629Forward primerTTAGAAGGAAACAGACCACAG ACCT
Reverse primerGTAGGACCCTGGAGGCTGAAC
Wild probeTET-TAGGTTTTGAGGGGCATGa GGACG-BHQ
Mutation probeFAM-TAGGTTTTGAGGGGCATGg GGAC-BHQ
rs1800750Forward primerCTTTCTGAAGCCCCTCCCA
Reverse primerTGCCCCTCAAAACCTATTGC
Wild probeTET-CCTGCATCCTGTC TGGAAaTTAGAAGGA-BHQ
Mutation probeFAM-CCTGCATCCTGTC TGGAAgTTAGAAGG-BHQ
rs1799964Forward primerCATTCCTCAGAGCCGCTACAT
Reverse primerGGGATATGTGATGGACTCACCAG
Wild probeTET-CTCCAGACCCTG ACTTTTCCTTCgTC-BHQ
Mutation probeFAM-CCTCCAGACCCTGA CTTTTCCTTCaTC-BHQ
rs673forward primerGGGTCCTACACACAAATCAGTC AGT
Reverse primerCCCTCACACTCCCCATCCT
Wild probeTET-AAGACCCCCCTCgGA-MGB
Mutation probeFAM-AAGACCCCCCTCaGA-MGB
Abbreviation: SNP, single nucleotide polymorphisms.

Experimental methods

Dilution of real-time PCR primers and probes such as TaqMan Universal Master Mix,TaqMan probe, and 10 ng of extracted DNA were mixed for each reaction. Polymerase chainreaction was performed according to the manufacture instruction. Each cycle included95°C 3-minute degeneration, 95°C 15-second degeneration, followed by −60°C annealing for1 minute. After a total of 40 cycles, the genotyping was performed. The examiner wasblinded from the grouping of the specimens.

Statistical Analysis

Hardy-Weinberg equilibrium test was performed using Haploview 4.2. The relationship ofgene polymorphism and disease susceptibility was analyzed using multiple logisticregression, and the odds ratios (ORs) were estimated. The allele frequency andgenotype–phenotype were compared between the cervical cancer group and the control groupand between the subgroup of patients with carcinoma in situ (CIS) and those with invasivecarcinoma (IC). The analysis was performed using SPSS version 17.0 and P< .05 was determined to be statistically significant.

Result

Comparison Between Cervical Cancer Group and the Control Group

There was statistical significance in Hardy-Weinberg balance test of cervical squamouscell carcinoma in the study of rs1800629 and rs1799964 loci (P < .05),the remaining 3 loci (rs361525, rs1800750, and rs673) compound Hardy-Weinberg balance test(P > .05), indicating that the samples were representative of thepopulation and that the 5 loci were independent of each other, and there is no geneticlinkage (linkage disequilibrium: r2 < 0.8). Statistical analysis also showed that the 2 groups were similar inthe general demographics, occupational history, history of pregnancy, and sexual behavior(χ2 = 1.623, P = .203; χ2 = 0.976,P = .323). However, the rate of high-risk HPV subtype infection inexfoliated cervical epithelial cells of patients with cervical cancer was significantlyhigher than that in the control group (91.4% vs 10.3%, P < .01). Therate of HPV infection in patients with CIS was lower than those with IC (77.9% vs 95.4%,P < .01; Table2).

Table 2.
Comparison of Demographics and HPV Infection Between Cervical Cancer Group, CISGroup, and Control Group.
GroupNAgeAge at First MarriagePregnancy (N)Delivery (N)Employed % (n)χ2/PaSmoking % (n)χ2/PaHPV Infection % (n)χ2/Pa
Cervical cancer45247.0 ± 14.524.5 ± 2.04.2 ± 2.02.4 ± 1.142.0% (190)19.9% (90)91.4% (413)
CIS10442.5 ± 8.525.0 ± 2.34.7 ± 1.72.2 ± 0.776.9% (80)χ2 = 1 62/P = .2032.7% (34)χ2 = 0.98/P = .3277.9% (81)χ2 = 620.4/P < .001
IC34849.7 ± 16.522.1 ± 3.74.3 ± 1.52.9 ± 1.628.6% (110)16.1% (56)95.4% (332)
Control49447.0 ± 15.524.8 ± 3.15.1 ± 2.82.3 ± 1.746.2% (228)17.4% (86)10.3% (51)
Abbreviations: CIS, carcinoma in situ; IC, invasive carcinoma; HPV, humanpapillomavirus.

a Used χ2 test.

Tumor Necrosis Factor-α Promoter Gene SNP Genotyping Test Results by Group

There was a significant difference in the rs361525 genotype (CC/CT/TT) between thecontrol, CIS, and IC groups (χ2 = 20.71, P < .001, Table 3). The same was true forrs1800629 and rs1799964 (GG/GA/AA; χ2 = 34.92, P < .001 andχ2 = 57.40, P < .001, respectively). There was nosignificant difference between the groups on rs1800750 and rs673 (all GG/GA/AA) genotypes(χ2 = 2.54, P = .28 and χ2 = 0.21,P = .90 > .05).

Table 3.

Results of TNF-α Promoter Gene SNP Genotype by Group.a

GroupNrs361525 (N)χ2/Pbrs1800629 (N)χ2/Pbrs1800750 (N)χ2/Pbrs1799964 (N)χ2/Pbrs673 (N)χ2/Pb
CCCTTTGGAGAAGGAGAAGGAGAAGGAGAA
Control49447519042470049220410813483110
Cervical squamous cell carcinoma452403490χ2 = 20.7073171350χ2 = 34.91645020χ2 = 2.5392751734χ2 = 57.396440120χ2 = 0.212
Carcinoma In situ1049770P < .00176280P < .00110400P = .28167371P < .00110130P = .899
Invasive carcinoma348306420241107034440212136333990
Abbreviations: TNF-α, tumor necrosis factor-α; SNP, single nucleotidepolymorphisms.

a C-cytosine; T-thymidine; A-adenine, and G-guanine. The base pair ofrs361525 gene is C and T, where CC and TT being homozygous and CT beingheterozygous; the base pair for other 4 SNP sites were all G, A, GG, and AA beinghomozygous, and AG being heterozygous.

b Used the Cochran-Mantel-Haenszel (CMH) test.

Single Nucleotide Polymorphism Allele Frequency of TNF-α Promoter in Cervical Cancerand Control Group

Allele frequencies of 5 SNPs (rs361525, rs1800629, rs1800750, rs1799964, and rs673) bystudy groups were summarized in Table4. Univariate logistic regression showed that the missense SNPs (rs361525,rs1800629, and rs1799964) were significantly correlated with cervical cancer. The C allelefrequencies of rs361525 in cervical cancer group and control group were 89.2% and 96.2%,respectively (OR = 0.33, 95% confidence interval [CI] = 0.19-0.57, P <.01). The frequency of T allele in cervical cancer group (10.8%) was also significantlyhigher than that in the control group (3.8%; OR = 3.04, 95% CI = 1.76-5.25,P < .01). rs1800629 had significant correlation with cervicalcancer: the G allele frequencies at rs1800629 locus in cervical cancer and control groupwere 70.1% and 85.8%, respectively (OR = 0.39, 95% CI = 0.28-0.54, P <.01). The A allele frequency was also higher in cervical cancer group (29.9%) than that inthe control group (14.2%; OR = 2.58, 95% CI = 1.87-3.56, P < .01).

Table 4.

Allele Frequencies of the 5 SNPs of TNF-α Promoter Gene by Groups.a

SNPsAllele frequencyχ2/PbOR (95% CI)P
Control group (N = 494)Cervical Cancer group (N = 452)
HomozygousHeterozygousHomozygousHeterozygousG/(C*)A/(T*)G/(C*)A/(T*)
rs3615250.962 (475)0.038 (19)0.892 (403)0.108 (49)χ2 = 17.3/P < .0010.33 (0.19-0.57)3.04 (1.76-5.25)<.01<.01
rs18006290.858 (424)0.142 (70)0.701 (317)0.299 (135)χ2 = 34.3/P < .0010.39 (0.28-0.54)2.58 (1.87-3.56)<.01<.01
rs18007500.996 (492)0.004 (2)0.996 (450)0.004 (2)χ2 = 0.008/P = 0.9291.09 (0.15-7.79)0.92 (0.13-6.52).929.929
rs17999640.836 (413)0.164 (81)0.617 (279)0.383 (173)χ2 = 57.52/P < .0010.32 (0.23-0.43)3.16 (2.33-4.28)<.01<.01
rs6730.978 (483)0.022 (11)0.973 (440)0.027 (12)χ2 = 0.182/P = 0.6690.84 (0.37-1.91)1.20 (0.52-2.74)0.66970.6697
Abbreviations: OR, odds ratio; SNP, single nucleotide polymorphisms; TNF-α, tumornecrosis factor-α.

a OR using the recessive genetic model (OR = 1, indicating that thefactor does not influence the occurrence of the disease; OR > 1, indicating thatthe factor is a risk factor; OR < 1, indicating that the factor is protectivefactors). The allele base of the rs361525 allele is C, T, CC, and TT beinghomozygous, CT being heterozygous; the other 4 sites are G, A, GG, and AA beinghomozygous, and AG being heterozygous.

b Used χ2 test.

rs1799964 SNP had a significant association with cervical cancer: G allele frequency atrs1799964 in cervical cancer group and control group were 61.7% and 83.6%, respectively(OR = 0.70, 95% CI = 0.52-0.94, P = .016). A allele frequency was alsohigher for the cervical cancer group (38.3%) than for the control group (16.4%; OR = 3.16,95% CI = 2.33-4.28, P = .016). This indicates that the high-risk alleleof rs361525 was TT + TC, and the nonrisk allele was CC; for rs1800629 and rs1799964, thehigh-risk allele was AG + AA, and the nonrisk allele was GG.

Comparison of Genotype and Allele Frequencies of 2 Loci in Patients With CervicalCarcinoma In Situ and Patients With Invasive Cervical Cancer

Among patients with cervical cancer, the comparison of the genotype (TT/TC/CC orGG/AG/AA) frequency and allele frequency (T/C or G/A) of the 5 loci between those with CISand those with IC only showed significant difference at rs1800629 (χ2 = 9.474,P = .002), and there was no difference at other 4 loci(P ≥ .05, Table5).

Table 5.
Comparison of Genotype and Allele Frequency of 5 Loci Between Patients With CIS andIC.
SNP LocusGroupNGenotype Frequency (%)χ2/PaAllele Frequency (%)χ2/Pb
CC/GGCT/GATT/AAC/GT/A
rs361525Carcinoma in situ10497 (93.3)7 (6.7)0 (0.0)χ2 = 2.356/P = .1248201 (96.6)7 (3.4)χ2 = 2.225/P = .1358
Invasive cancer348306 (87.9)42 (12.1)0 (0.0)654 (94.0)42 (6.0)
rs1800629Carcinoma in situ10476 (73.1)28 (26.9)0 (0.0)χ2 = 0.558/P = .4552180 (86.5)28 (13.5)χ2 = 9.474/P = .002
Invasive cancer348241 (69.3)107 (30.7)0 (0.0)589 (93.3)42 (6.7)
rs1800750Carcinoma in situ104104 (100.0)0 (0.0)0 (0.0)χ2 = 1.203/P = .2726208 (100.0)0 (0.0)P = .5790c
Invasive cancer348344 (98.9)4 (1.1)0 (0.0)692 (99.4)4 (0.6)
rs1799964Carcinoma in situ10466 (64.3)37 (35.6)1 (0.01)χ2 = 0.414/P = .8117171 (81.4)39 (18.6)χ = 0.279/P = .5971
Invasive cancer348209 (60.0)136 (39.1)3 (0.9)692 (83.0)142 (17.0)
rs673Carcinoma in situ104101 (97.1)3 (2.9)0 (0.0)χ2 = 028/P = .8682205 (98.6)3 (1.4)χ2 = 0.000/P = 1.000d
Invasive cancer348339 (98.9)9 (1.1)0 (0.0)692 (98.7)9 (1.3)
Abbreviations: CIS, carcinoma in situ; IC, invasive carcinoma; SNP, singlenucleotide polymorphisms.

a Using Cochran-Mantel-Haenszel (CMH) test.

b Using χ2 test.

c Using Fisher test.

d Use continuity correction card.

Discussion

Based on the information from HapMap database, this is the first study that investigatedthe association between genotype and allele frequency at 5 SNP loci of TNF-α promoter(rs361525, rs1800629, rs1800750, rs1799964, and rs673) and the risk of cervical cancer inShandong province, China.

The study found that the rate of high-risk HPV subtype infection in exfoliated cervicalepithelial cells was significantly higher for patients with cervical cancer than the controlgroup; the rate of HPV infection in patients with CIS was also significantly lower than thatin the patients with IC. The genotype of rs191525 (CC/CT/TT) was significantly differentbetween control, CIS, and IC groups. So were rs1800629 and rs1799964 (GG/GA/AA), and therewas no significant difference between these groups at rs1800750 and rs673 loci (GG/GA/AA).Compared to the control group, the SNPs of rs361525, rs1800629, and rs1799964, which weremissense mutation and can cause amino acid change, were significantly correlated withcervical cancer risk. The frequency of C allele at rs361525 was lower in cervical cancergroup than in the control group, but the frequency of T allele was higher in cervical cancergroup.

rs1800629 genotype was shown to be associated with cervical cancer: The frequency of Gallele at this locus was lower in cervical cancer group than control group, while thefrequency of A allele was significantly higher in patients with cancer than the controlgroup (OR = 2.58, 95% CI = 1.87-3.56). rs1799964 genotype was also shown to be associatedwith the cervical cancer risk. G allele frequency at rs1799964 locus was lower, but thefrequency of A allele was significantly higher in patients with cervical cancer than thosein the control group. The risk allele at rs361525 locus was TT + TC, and the nonrisk allelewas CC. The risk allele for rs1800629 and rs1799964 was AG + AA, and the nonrisk allele wasGG.

The possible explanation for the rs361525, rs1800629, and rs1799964 SNP mutation andincreased susceptibility to cervical cancer is that, the alteration in the frequencies ofthe genotype and allele at these 3 loci may change the level of TNF-α expression and affectthe body’s immune system, which leads to the increased risk of persistent HPV infection, themain risk factor of cervical cancer, and thus becomes carcinogenic. This has been confirmedin other cancer researches.

Johnson et al reported that the risk of cervical cancer is associated withgenetic polymorphisms in chromosome 5 cytokine clusters.34 De Oliveira and colleagues studied the 10 SNP loci, including TNF-α (rs1799724), in669 cases of digestive tract malignancies, found that genotype G/A of TNF-α was notassociated with the risk of gastrointestinal malignancy, whereas C/T genotype was (TNF-a-857C/T, P = .022), suggesting that the interaction between the inflammatoryprocess and the SNP is a potential contributor to the occurrence of gastrointestinal cancer.31 However, Danforth and others reported that abnormal SNPs (rs1799724) at the TNF siteand long-term inflammatory stimuli were not associated with the increased risk of prostate cancer.35 In this study, the infection by high-risk HPV subtype in cervical exfoliatedepithelial cells was prevalent (91.4%). Cervical inflammatory lesions and cervicalintraepithelial neoplasia (CIN) due to the HPV infection,5,6 in combination with abnormalities of genotype and allele frequency at rs361525,rs1800629, and rs1799964 loci, may be one of major contributing factors for the occurrenceof cervical cancer.

In other researches of rs361525 polymorphisms and cervical cancer, the results were controversial.28,29 In certain ethnic groups, rs1800629 polymorphism was shown to be associated with anincreased risk of cervical cancer,2427 but in the study of different ethnicity, this relationship was not identified.36 In Mexican, a study found that rs1800750 polymorphism was protective forintraepithelial neoplasia, and rs1799964 and rs673 were neutral.25

In summary, rs361525, rs1800629, and rs1799964 were all shown in this study to beassociated with increased risk of cervical cancer in Chinese women of Han ethnicity.Patients with these SNP loci abnormalities and infected by HPV represent a high-riskpopulation for cervical cancer and should be given more attention for prevention and earlydetection. Finally, it should be noted that the patients with cervical cancer enrolled inthis study were limited to squamous cell carcinoma. Future study should be considered toconfirm this study findings in patients with adenocarcinoma and CIN.

Footnotes

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) received no financial support for the research, authorship, and/orpublication of this article.

Abbreviations

CIconfidence intervalCINcervical intraepithelial neoplasiaCIScarcinoma in situHPVhuman papillomavirusICinvasive carcinomaORodds ratioSNPsingle nucleotide polymorphismsTNF-αtumor necrosis factor-α

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